2′-fluoro-6′-methylene carbocyclic nucleosides and methods of treating viral infections

ABSTRACT

The present invention relates to 2′-Fluoro-6′-methylene carbocyclic nucleosides, pharmaceutical compositions containing these nucleosides and their use in the treatment or prophylaxis of a number of viral infections and secondary disease states and conditions thereof, especially including Hepatitis B virus (HBV) and secondary disease states and conditions thereof (cirrhosis and liver cancer), Heptatitis C virus (HCV), Herpes Simplex virus I and II (HSV-1 and HSV-2), cytomegalovirus (CMV), Varicella-Zoster Virus (VZV) and Epstein Barr virus (EBV) and secondary cancers which occur thereof (lymphoma, nasopharyngeal cancer, including drug resistant (especially including lamivudine and/or adefovir resistant) and other mutant forms of these viruses.

CLAIM OF PRIORITY AND GOVERNMENT RIGHTS

The present application is a continuation-in-part application ofinternational application PCT/US10/56808, filed 16 Nov. 2010, entitled“2′-Fluoro-6′-Methylene Carbocyclic Nucleosides and Methods of TreatingViral Infections”, which itself claims priority to U.S. provisionalapplication 61/281,342, filed Nov. 16, 2009, entitled“2′-Fluoro-6′-Methylene Carbocyclic Nucleosides and Methods of TreatingViral Infections”, the entire contents of all of which applications areincorporated by reference herein.

The work which gave rise to this patent application was supported byU.S. Public Health Search Grant no. AI25899 from the National Instituteof Allergy. Consequently, the government retains certain rights in theinvention.

FIELD OF THE INVENTION

The present invention relates to 2′-Fluoro-6′-methylene carbocyclicnucleosides, pharmaceutical compositions containing these nucleosidesand their use in the treatment or prophylaxis of a number of viralinfections and secondary disease states and conditions thereof,including Hepatitis B virus (HBV) and secondary disease states andconditions thereof (cirrhosis and liver cancer), including liver cancer,Heptatitis C virus (HCV), Herpes Simplex virus I and II (HSV-1 andHSV-2), cytomegalovirus (CMV), Varicella-Zoster Virus (VZV) and EpsteinBarr virus (EBV), including drug resistant (especially includinglamivudine and/or adefovir resistant) and other mutant forms of theseviruses. The use of 2′-Fluoro-6′methylene-carbocycolic adenosine (FMCA,compound 15/18) and its monophosphate prodrug (phosphoamidate) (compound15P) exhibits excellent activity against HBV and in particular, drugresistant forms of HBV, especially HBV resistant to lamivudine and/oradefovir anti-HBV agents. The prodrug form in particular wasunexpectedly found to be exceptionally active against drug resistantforms of HBV.

BACKGROUND OF THE INVENTION

Hepatitis B virus (HBV) infection is one of major global healthproblems.¹ Although primary HBV infections in most adults areself-limited, 3-5% patients do not resolve and develop into chronicinfection and this rate is much higher among young children infectedwith HBV.² The estimated number of the chronic hepatitis B (CHB)carriers is approximately 350-400 million worldwide, with more than onemillion deaths annually resulted from cirrhosis, liver failure andhepatocellular carcinoma.²

Agents currently available for the treatment of HBV infection can beclassified into two main categories: immunomodulator andnucleoside/nucleotide analogues. Although the efficacy of INF α, arepresentative immunomodulator, has been established by a numerousstudies, the clinical application of INFα has been compromised by thelow overall response rate, side effects and high cost.^(3,4)Nucleoside/nucleotide analogs, on the hand, continue to dominate theanti-HBV therapy. There are at least six nucleosides/nucleotides in theclinical use, including lamivudine (Epivir-HBV®, GlaxoSmithKline),adefovir dipivoxil (Hepsera®, Gilead), entecavir (Baraclude®,Bristol-Myers Squibb), telbivudine (Tyzeka®, Idenix/Novartis), clevudine(Levovir® in South Korean, Phase III in US, Bukwang/Pharmasset) and mostrecently tenofovir (Viread®, Gilead). (FIG. 1). These agentssignificantly suppress the replication of HBV DNA to a lowest possiblelevel which leads to the favorable clinical outcomes and preventsadvanced liver sequelae. Indeed, the introduction of these oralnucleosides/nucleotides is the breakthrough in the anti-HBV therapy. Ithas been reported that the number of patients in US registered for livertransplantation has been decreased 30% since widespread application ofnucleoside anti-HBV agents.⁵

There is no solid evidence that current nucleosides/nucleotidestreatments have direct effect on the HBV covalently closed circular DNA(cccDNA), which has a long half-life and is believed to serve as thetranscriptional template as long as the termination of the therapy,⁶leading to the viral DNA rebound. Consequently, long-term, highlyeffective antiviral therapy may be required to prevent viral relapsefollowing discontinuation of the treatment.⁷ Unfortunately, long-termnucleosides/nucleotides treatment is always associated with thedevelopment of drug-resistant mutants which significantly compromisedthe efficacy. The nature of HBV polymerase coupled with high replicationrate lead to the emergence of HBV mutants which have survival advantagein the presence of certain antiviral agents.⁸ The current use oflamivudine, the first approved anti-HBV nucleoside, has been limited bythe high frequency of lamivudine resistance (most commonlyrtL180M±rtM204V/I). The in vitro study indicated rtL180M+rtM204V/Imutations result in a >1000-fold decreased susceptibility of the virusto lamivudine without significant impairing of polymerasefunction.^(9,10) In clinical practice, the approximate rate ofresistance of lamivudine is about 20% at the end of 1-year and 70% after5-year treatment.¹¹⁻¹⁴ Telbivudine, another L-nucleoside, iscross-resistant to the major lamivudine mutation at YMDD motif,represented by the rtM204I. It is associated with a lower rate ofresistance compared to lamivudine after 1 year therapy (around 5% inHBeAg-postive patients), while the rate jumps to 22% after 2 years.¹⁵These data may indicate a possible high rate of drug-resistance in thelonger duration of telbivudine therapy. Adefovir belongs to the acyclicphosphonate. Bearing distinct acyclic sugar moieties, this nucleoside isnot cross-resistant to the L-nucleosides. However, there are two primaryadefovir-resistant mutations at codon 181 (rtA181T) and codon 236(rtN236T) which result in two-fold to nine-fold increase in medianeffective concentration.¹⁶⁻¹⁸ Although the fold of increase is modest,reports showed non-response to the adefovir treatment is associated withthree patients who developed a mutation.^(19,20) The rate of developingresistance with adefovir treatment is also significant high, with about3% at 2 years and 29% at 5 years.²¹ The other potent anti-HBVnucleoside, entecavir, has a high genetic barrier to resistance.However, in patients with pre-existing lamivudine-resistant mutations,the probability of entecavir resistance increases from 1% at 1 year to51% to 5 years.^(22,23) Therefore, entecavir is not recommended asmonotherapy in patients with YMDD mutations. Although there is no solidevidence of detecting resistance to date after continuous treatment withtenofovir or clevudine in clinical, results after prolonged therapyremain to be determined.

The development of antiviral resistance is generally associated withworse clinical outcomes.⁸ For example, the efficacy of lamivudinetreatment was negated by the development of drug resistance.²⁴ Patientswho developed drug resistance were less likely to demonstratehistological improvement (44% versus 77%) and more likely to show liverdeterioration (15% versus 5%) in comparison to subjects who have noevidence of drug resistance.²⁴ Particularly, there have been reportedhepatitis flares and hepatic decomposition in patients following thedevelopment of antiviral resistance.²⁵ Therefore, a careful managementof antiviral resistance is paramount in the anti-HBV treatment. Add-on(combination with different nucleosides or interferon) therapy andswitching to an alternative nucleoside monotherapy are two major optionsfor patients with suboptimal response to the initial single nucleosidetreatment. Although it is not clear which is the most effective way inthe management of resistance, providing additional/alternative agentswith high genetic barrier and with different resistance profile from theinitial drug are critical, Current anti-HBV arsenal is limited.Therefore it is important to develop novel nucleoside analogs which areactive against not only wild type (WT) but also existing HBVdrug-resistant mutants. During the course of our drug discoveryprograms, introduction of fluorine atom onto the sugar moiety generateda number of novel nucleosides with interesting biological interestingnucleosides.²⁶⁻³⁵ Therefore, it is of great interest to explore thesubstitution of fluorine atom on the carbocyclic nucleosides with an6′-exo-cyclic alkene (6′-methylene). Herein, we would like to report theinvention of the interesting fluorinated carbocyclic nucleoside which isactive against HBV-WT as well as lamivudine- and adefovir-resistantmutants.

The search for antiviral agents treatment of Hepatitis B virus,Hepatitis C virus, Herpes Simplex virus I and II (HSV I and II),cytomegalovirus (CMV), Varicella-Zoster Virus (VZV) and Epstein Barrvirus is an ongoing process and the present invention is directed tothose viral disease states.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a number of current anti-HBV nucleosides/nucleotides.

FIG. 2 shows (a) Low-energy conformer of modeled nucleoside 16(indicated in blue) adopted a 2′-endo, Southern conformation. Althoughthis conformer is not global minimum, the energy barrier between them isas low as 0.5 kJ/mol. (b) The superimposed the structures of 16 and 15indicated the similarity between the conformations of two molecules. (c)Fluorinated carbocyclic nucleoside 15 (C: gray, N: blue, O: red, F:green, H: white) also preferred a 2′-endo, Southern conformation.

FIG. 3 shows synthetic scheme 1, which provides a series of syntheticsteps to sugar synthon intermediate 10. The following reagents andconditions were used: (a) Ref. 33, 34, 40; (b) i) LDA, Echenmoser'ssalt, THF, −78° C., ii) MeI, rt, iii) sat. NaHCO₃ solution, rt; (c)NaBH₄/CeCl₃.7H₂O, THF, −78° C.; (d) NaH, BnBr, TBAI, THF, rt; (e) 3NHCl, MeOH, 90° C.; (f) TIPDSCl, Py, −30° C. to rt; (g) DAST, CH₂Cl₂, rt;(h) Tf₂O, Py, −30° C. to rt, ii) CeOAc, 18-Crown-6, benzene, 50° C.;iii) NaOMe, MeOH, rt; (i) i) TBAF/HOAc, THF, rt, ii) B_(Z)Cl, Py, rt;(j) BCl₃, CH₂Cl₂, −78° C.

FIG. 4 shows synthetic scheme 2, which provides a series of syntheticsteps to nucleoside compound 15. The following reagents and conditionswere used; (a) DIAD, Ph₃P, 6-chloropurine, THF, rt; (b) NH₃, MeOH, 100°C. or NaN₃, DMF followed by H₂O; (c) i) OsO₄/NMO, Acetone/H₂O, rt, ii)NaN₃, DMF, 140° C., iii) H₂/Pd/C, EtOH, rt; (d) i)1-bromocarbonyl-1-methylethyl acetate, acetonitrile, −30° C.—rt, ii)Zn/HOAc, DMF, rt; (e) DIBAL-H, CH₂Cl₂, −78° C.

FIG. 5 shows alternative scheme 2, which provides a series of syntheticsteps to compound 15/18, which was used in testing against wild-type andmutant HBV as described in the examples section. The following reagentsand conditions were used: (a) see Jin, et al., J. Org. Chem., 2003, 68,9012-9018 (b) i) LDA, Eshenmoser's salt, THF, −78° C.; ii) MeI, rt; iii)sat. NaHCO₃ solution, rt; (c) NaBH₄/CeCl₃.7H₂O, MeOH, −78° C.; (d) NaH,BnBr, DMF, 0° C.; (e) TFA/H₂O (2:1), 50° C.; (f) TIDPSCl₂/Imidazole,DMF, 0° C.; (g) DAST, CH₂Cl₂, rt; (h) TBAF/AcOH, THF, rt; (i) BzCl,Pyridine, rt; (j) Bab, CH₂Cl₂, −78° C.

FIG. 6 shows yet another alternative chemical scheme, which provides aseries of synthetic steps to compound 15/18. This is an abbreviatedmethod as the synthesis as otherwise provided herein.

FIG. 7 shows alternative scheme 3, which provides a series of syntheticsteps to compound 15/18. The following reagents and conditions are used:(a) i) OsO₄/NMO, Acetone/water (ii) dimethoxy propane, PTSA, Acetone (b)NaBH₄, Methanol (c) tert-butyl chloride, NaH, DMF (d), TFA, DCM orNaO^(t)Bu, H₂O/THF (e) NBS, NaOMe, ethanol, H⁺ (f) (i) LDA, Eshenmoser'ssalt, THF, −78° C.; ii) MeI, rt; iii) sat. NaHCO₃ solution, rt; (g)NaBH₄/CeCl₃.7H₂O, MeOH (h) NaH, BnBr, DMF, (i) TFA/H₂O (2:1), 50° C.;(j) TIDPSCl₂/Imidazole, DMF; (k) DAST, CH₂Cl₂, (l) BCl₃, CH₂Cl₂; (m)DIAD, Ph₃P,THF; (m) TFA, CH₂Cl₂.

FIG. 8 shows the prodrug synthesis of compound 15P/18P and 15PI/18PI.The synthesis proceeds from the dichlorophosph 1P by reacting L-alaninesubstituted ester hydrochloride in the presence of triethylamine inmethylene chloride solvent to produce 2P or 3P, the methyl ester orisopropyl ester of chlorophenylphosphoryl-L-alaninate. To the phosphorylintermediate 2P or 3P, is added compound 15/18 in N-Methylimidazole indry tetrahydrofuran overnight to produce the prodrug analogs 15P/18P and15PI/18PI as indicated. It is noted that while the methyl and isopropylester 15P/18P and 15PI/18PI are shown, the corresponding ethyl andisobutyl esters are also made via the same procedure. The synthesis inFIG. 8 shows a diasteromeric mixture of compounds (both the carbonexhibiting a stereospecific methyl on the alanine group and thephosphorous group are chiral centers, but the phosphorous group shown isracemic, resulting in a diastereomeric mixture of compounds). Thesediastereomers are readily separated using standard methods available inthe art including selective crystallization techniques and/or chiralcolumns.

FIG. 9 shows a rough schematic of the chemical schemes otherwisedisclosed in the present specification. The present synthesis providesan approach to synthesizing compounds according to the present inventionfrom D-ribose as indicated.

FIG. 10 shows in vitro anti-HBV activity of compound 15/18 againstlamivudine and adefovir drug-resistant mutants on the intracellular HBVDNA replication assay. The figure legend for Table 1 is as follows: ^(a)rtLM/rtMV=rt180M/rtM204V double mutant. ^(b)Effective concentrationrequired to inhibit 50% of HBV-DNA. ^(c)Concentration required to reduceinfectious virus titer by 90%. ^(d)The > sign indicates that the 50%inhibition was not reached at the highest concentration tested. ^(e)Thedrug concentration required to reduce the viability of cell asdetermined by MTT assay by 50% of untreated control after 3 day.

FIG. 11 shows Table 2 setting forth the in vitro anti-HBV activitycompound 15/18, its monophosphate prodrug 15P/18P, lamivudine andentecavir against wild type and entecavir drug-resistant mutant in Huh7cells. ^(a) see reference (22); ^(b)reference (23) of second set ofreferences.

FIGS. 12A and 12B shows the anti-HBV activity of compound 15P/18Pagainst HBV genotype C entacavir resistant clone (L180M+S202G+M204V) inHuh7 cells. FIG. 12B shows the IC₅₀ value of compound 15/18 of 0.054 μM.

FIG. 13 shows the mitochondrial toxicity of compound 15/18, AZT and 3TCthrough lactase dehydrogenase release (LDH) assay.

FIG. 14 shows the binding mode and van der. Waals interaction ofcompound 15/18 a) in wild-type HBV and b) in N236T adefovir mutant HBV.Yellow dotted lines are hydrogen bonding interactions (<2.5 Å).

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to carbocyclic nucleoside compoundsaccording to the structure:

Where B is

Wherein R is H, F, Cl, Br, I, C₁-C₄ alkyl (preferably CH₃), —C≡N,—C≡C—R_(a),

X is H, C₁-C₄ alkyl (preferably, CH₃), F, Cl, Br or I;R_(a) is H or a —C₁-C₄ alkyl group;R¹ and R^(1a) are each independently, H, an acyl group, a C₁-C₂₀ alkylor ether group, an amino acid residue (D or L), a phosphate,diphosphate, triphosphate, phosphodiester or phosphoamidate group ortogether R¹ and R^(1a) form a carbodiester, phosphodiester orphosphoamidate group with the oxygen atoms to which they are bonded;R² is H, an acyl group, a C₁-C₂₀ alkyl or ether group or an amino acidresidue (D or L);Or a pharmaceutically acceptable salt, enantiomer, hydrate or solvatethererof.

Preferably R^(1a) is H. Also preferably, R¹ and R² are eachindependently H or a C₂-C₂₀ acyl group, more preferably both are H. Incertain aspects R¹ is a phosphoamidate group.

B is preferably

In alternative preferred aspects, the compound is represented by thechemical structure:

-   -   Where B is as described above, preferably

and R¹, R^(1a) and R² are as otherwise described hereinabove. Note thatthe fluoro group at the 2′ position (which may be disposed in an alphaor beta configuration in compounds according to the present invention)is preferably disposed in a beta (upward) configuration as depicted.Preferred compounds according to the present invention are prodrug formswhere R^(1a) is a phosphoamidate group as otherwise described herein,preferably a phosphoamidate group derived from an amino acid asotherwise described herein. In certain aspects, a particularly preferredR¹ group is the phosphoamidate group

Where R_(p1) is an optionally substituted (OH, halo) C₁-C₂₀ alkyl group,preferably a C₁-C₄ alkyl group, even more preferably a methyl, ethyl,isopropyl group or isobutyl group; and R^(P) is H, nitro, cyano,methoxy, or a C₁-C₃ alkyl group optionally substituted with from 1-3halogen substituents (preferably F). The present invention is alsodirected to individual diastereomers based upon the phosphoamidate groupas otherwise described herein (phosphorous is a chiral center).

Preferred phosphoamidate groups for R¹ include those according to thechemical structure:

Where R^(P) is H or C₁-C₃ alkyl group and R_(p1) is methyl, ethyl,isopropyl or isobutyl, more preferably a methyl or isopropyl group.Preferably, R¹ is a

group.

In particularly preferred aspects of the invention, the anti-HBVcompound for use in the present invention is.

Or a pharmaceutically acceptable salt thereof.

The present invention also relates to pharmaceutical compositionscomprising an effective amount of a compound as described above,optionally in combination with a pharmaceutically acceptable carrier,additive or excipient. Alternative embodiments of pharmaceuticalcompositions comprise an effective amount of a carbocyclic nucleosidecompound as otherwise described herein in combination with an additionalantiviral agent. Preferred antiviral agents include, for exampleacyclovir, famciclovir, ganciclovir, valaciclovir, vidaribine,ribavirin, zoster-immune globulin (ZIG), lamivudine, adefovir dipivoxil,entecavir, telbivudine, clevudine, tenofovir and mixtures thereof.Particularly preferred compounds for use in the pharmaceutical aspect ofthe present invention include

Or a pharmaceutically acceptable salt thereof.

Methods of treatment represent further embodiments according to thepresent invention. In this aspect a method of treating or reducing thelikelihood of a viral infection, wherein the viral infection is causedby Hepatitis B virus (HBV), Hepatitis C virus (HCV), Herpex Simplex I(HSV I), Herpes Simplex II (HSV II), Cytomegalovirusx (CMV), VaricellaZoster Virus (VZV) or Epstein Barr Virus (EBV), comprises administeringto a patient in need of therapy or at risk for infection thereof aneffective amount of a compound as otherwise described above.

In method aspects of the present invention, preferred compounds for usein the present to treat HBV include:

Or a pharmaceutically acceptable salt thereof.

In a preferred method, the present invention relates to a method oftreating a HBV infection, including a drug resistant (further includingmultiple drug resistant) HBV infection, wherein the drug resistance isto any one or more of currently used anti-HBV agents, includingadefovir, entecavir and/or lamivudine drug resistance, especiallyincluding strains resistant to lamivudine and entecavir, lamivudine andadefovir, entecavir and limuvidine and lamivudine, entecare andadefovir, among others. In this aspect of the invention, preferredcompounds for use in the present method to treat a HBV infection,especially including a drug resistant (including a multiple drugresistant as described hereinabove) HBV infection include:

Or a pharmaceutically acceptable salt thereof.

Combination therapy using the present compounds in combination with anadditional antiviral agent represent additional aspects of the presentinvention. Preferred antiviral agents include, for example acyclovir,famciclovir, ganciclovir, valaciclovir, vidaribine, ribavirin,zoster-immune globulin (ZIG), lamivudine, adefovir dipivoxil, entecavir,telbivudine, clevudine, tenofovir and mixtures thereof, including otheragents as otherwise described herein. Methods of treating or reducingthe likelihood of the development of fibrosis, liver cancer or cirrhosissecondary to a viral infection, including a drug resistant viralinfection (especially including HBV and/or HCV) represent additionalaspects of the present invention. The use of the following compounds(including their diasteromerically enriched and/or diastereomericallypure compounds) in certain aspects of combination therapy for thetreatment of a HBV infection, especially including a drug resistant(including a multiple drug resistant as otherwise described herein)strain of HBV, are particularly preferred:

Or a pharmaceutically acceptable salt thereof in combination with anyone or more additional anti-HBV agents as otherwise described herein.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used to describe the invention. If a termis not specifically defined herein, the meaning given to the term isthat which one of ordinary skill would apply to the term within thecontext of the term's use.

The term “compound”, as used herein, unless otherwise indicated, refersto any specific chemical, compound disclosed herein, generally refers toβ-D nucleoside analogs, but may include, within context, tautomers,regioisomers, geometric isomers, anomers, and where applicable, opticalisomers (enantiomers) or diastereomers (two chiral centers) thereof ofthese compounds, as well as pharmaceutically acceptable salts thereof,solvates and/or polymorphs thereof. Within its use in context, the termcompound generally refers to a single compound, but also may includeother compounds such as stereoisomers, regioisomers and/or opticalisomers (including racemic mixtures and/or diastereomers as describedherein) as well as specific enantiomers, enantiomerically enriched orindividual diastereomers or mixtures of disclosed compounds. It is notedthat in the event that a carbon range is provided for a compound, thatrange signifies that each and every carbon individually is consideredpart of the range. For example a C₁-C₂₀ group describes a group with asingle carbon, two carbon atoms, three carbon atoms, four carbon atoms,etc. up to twenty carbons.

The term “patient” or “subject” is used throughout the specification todescribe an animal, preferably a domesticated animal or a human, morepreferably a human to whom treatment, including prophylactic treatment,with the compositions according to the present invention is provided.For treatment of those infections, conditions or disease states whichare specific for a specific animal such as a human patient, the termpatient refers to that specific animal. In general, in the presentinvention, the term patient refers to a human patient unless otherwisestated. In the present invention, in addition to humans, domesticatedanimals (e.g., horses, cows, dogs, cats, etc.) also may be commonlytreated.

The term “Hepatitis B virus” or “HBV” is used to describe a virus whichinfects the liver of hominoidae, including humans, and causes aninflammation called hepatitis. Originally known as “serum hepatitis”,the disease has caused epidemics in parts of Asia and Africa, and it isendemic in China. About a third of the world's population, more than 2billion people, have been infected with the hepatitis B virus. Thisincludes 350 million chronic carriers of the virus. Transmission ofhepatitis B virus results from exposure to infectious blood or bodyfluids containing blood. The acute illness causes liver inflammation,vomiting, jaundice and—rarely—death. Chronic hepatitis B may eventuallycause liver cirrhosis and liver cancer—a fatal disease with very poorresponse to current chemotherapy.

Hepatitis B virus is an hepadnavirus—hepa from hepatotrophic and dnabecause it is a DNA virus and it has a circular genome composed ofpartially double-stranded DNA. The viruses replicate through an RNAintermediate form by reverse transcription, and in this respect they aresimilar to retroviruses. Although replication takes place in the liver,the virus spreads to the blood where virus-specific proteins and theircorresponding antibodies are found in infected people. Blood tests forthese proteins and antibodies are used to diagnose the infection.

Cirrhosis of the liver and liver cancer may ensue from a Hepatitis Bvirus infection. The hepatitis B virus primarily interferes with thefunctions of the liver by replicating in liver cells, known ashepatocytes. The primary method of transmission reflects the prevalenceof chronic HBV infection in a given area. In low prevalence areas suchas the continental United States and Western Europe, where less than 2%of the population is chronically infected, injection drug abuse andunprotected sex are the primary methods, although other factors may beimportant. In moderate prevalence areas, which include Eastern Europe,Russia, and Japan, where 2-7% of the population is chronically infected,the disease is predominantly spread among children. In high prevalenceareas such as China and South East Asia, transmission during childbirthis most common, although in other areas such as Africa, transmissionduring childhood is a significant factor. The prevalence of chronic HBVinfection in certain areas may be at least 8%.

Transmission of hepatitis B virus results from exposure to infectiousblood or body fluids containing blood. Possible forms of transmissioninclude (but are not limited to) unprotected sexual contact, bloodtransfusions, re-use of contaminated needles & syringes, and verticaltransmission from mother to child during childbirth.

Compounds which have been shown to be useful in the treatment and/orinhibition of HBV infections and which may be combined with2′-fluoronucleoside compounds according to the present invention for thetreatment of HBV infections include, for example, Hepsera (adefovirdipivoxil), lamivudine, entecavir, telbivudine, tenofovir,emtricitabine, clevudine, valtoricitabine, amdoxovir, pradefovir,racivir, BAM 205, nitazoxanide, UT 231-B, Bay 41-4109, EHT899, zadaxin(thymosin alpha-1), and mixtures thereof. The term “drug resistant” or“drug resistant mutants” of HBV includes all strains of HBV which areresistant to one or more (including multiple drug resistant strains) ofthe above-referenced anti-HBV agents, especially including one or moreof lamivudine, adefovir and entecavir. These strains include, forexample, HBV strains rtM204V, rtM204I, rt180M, rtLM/rtMV (which is adouble mutant of rt180M/rtM204V), rtN236T, L180M+S02I+M202V (anentecavir mutant), among others. The present compounds are usefulagainst all types of drug resistant HBV strains, including multiple drugresistant strains.

The term “Hepatitis C virus” or “HCV” is used to describe a virus whichcauses a Hepatitis C infection, which is an infectious disease of theliver. The infection is often asymptomatic, but once established,chronic infection can progress to scarring of the liver (fibrosis), andadvanced scarring (cirrhosis) which is generally apparent after manyyears. In some cases, those with cirrhosis will go on to develop liverfailure or other complications of cirrhosis, including liver cancer.

The hepatitis C virus (HCV) is spread by blood-to-blood contact. Mostpeople have few, if any symptoms after the initial infection, yet thevirus persists in the liver in about 85% of those infected. Those whodevelop cirrhosis or liver cancer may require a liver transplant, andthe virus universally recurs after transplantation.

An estimated 270-300 million people worldwide are infected withhepatitis C. Hepatitis C is a strictly human disease. It cannot becontracted from or given to any animal, although experiments onchimpanzees are possible. Acute hepatitis C refers to the first 6 monthsafter infection with HCV. Between 60% and 70% of people infected developno symptoms during the acute phase. In the minority of patients whoexperience acute phase symptoms, they are generally mild andnonspecific, and rarely lead to a specific diagnosis of hepatitis C.Symptoms of acute hepatitis C infection include decreased appetite,fatigue, abdominal pain, jaundice, itching, and flu-like symptoms.Hepatitis C virus is usually detectable in the blood within one to threeweeks after infection by PCR, and antibodies to the virus are generallydetectable within 3 to 15 weeks. Spontaneous viral clearance rates arehighly variable and between 10-60% of persons infected with HCV clearthe virus from their bodies during the acute phase as shown bynormalization in liver enzymes (alanine transaminase (ALT) & aspartatetransaminase (AST)), and plasma HCV-RNA clearance (this is known asspontaneous viral clearance). However, persistent infections are commonand most patients develop chronic hepatitis C, i.e., infection lastingmore than 6 months. Previous practice was to not treat acute infectionsto see if the person would spontaneously clear; recent studies haveshown that treatment during the acute phase of genotype 1 infections hasa greater than 90% success rate with half the treatment time requiredfor chronic infections.

Chronic hepatitis C is defined as infection with the hepatitis C viruspersisting for more than six months. Clinically, it is oftenasymptomatic (without symptoms) and it is mostly discoveredaccidentally. The natural course of chronic hepatitis C variesconsiderably from one person to another. Although almost all peopleinfected with HCV have evidence of inflammation on liver biopsy, therate of progression of liver scarring (fibrosis) shows significantvariability among individuals. Accurate estimates of the risk over timeare difficult to establish because of the limited time that tests forthis virus have been available. Recent data suggest that among untreatedpatients, roughly one-third progress to liver cirrhosis in less than 20years. Another third progress to cirrhosis within 30 years. Theremainder of patients appear to progress so slowly that they areunlikely to develop cirrhosis within their lifetimes. In contrast theNIH consensus guidelines state that the risk of progression to cirrhosisover a 20-year period is 3-20 percent.

Factors that have been reported to influence the rate of HCV diseaseprogression include age (increasing age associated with more rapidprogression), gender (males have more rapid disease progression thanfemales), alcohol consumption (associated with an increased rate ofdisease progression), HIV coinfection (associated with a markedlyincreased rate of disease progression), and fatty liver (the presence offat in liver cells has been associated with an increased rate of diseaseprogression).

Symptoms specifically suggestive of liver disease are typically absentuntil substantial scarring of the liver has occurred. However, hepatitisC is a systemic disease and patients may experience a wide spectrum ofclinical manifestations ranging from an absence of symptoms to a moresymptomatic illness prior to the development of advanced liver disease.Generalized signs and symptoms associated with chronic hepatitis Cinclude fatigue, flu-like symptoms, joint pains, itching, sleepdisturbances, appetite changes, nausea, and depression.

Once chronic hepatitis C has progressed to cirrhosis, signs and symptomsmay appear that are generally caused by either decreased liver functionor increased pressure in the liver circulation, a condition known asportal hypertension. Possible signs and symptoms of liver cirrhosisinclude ascites (accumulation of fluid in the abdomen), bruising andbleeding tendency, varices (enlarged veins, especially in the stomachand esophagus), jaundice, and a syndrome of cognitive impairment knownas hepatic encephalopathy. Hepatic encephalopathy is due to theaccumulation of ammonia and other substances normally cleared by ahealthy liver.

Hepatitis C infection livers show variable elevation of ALT and AST inliver tests. Periodically they might show normal results. Usuallyprothrombin and albumin results are normal, but may become abnormal,once cirrhosis has developed. The level of elevation of liver tests donot correlate well with the amount of liver injury on biopsy. Viralgenotype and viral load also do not correlate with the amount of liverinjury. Liver biopsy is the best test to determine the amount ofscarring and inflammation. Radiographic studies such as ultrasound or CTscan do not always show liver injury until it is fairly advanced.However, non-invasive tests (blood sample) are coming, with FibroTestand ActiTest, respectively estimating liver fibrosis andnecrotico-inflammatory. These tests are validated and recommended inEurope (FDA procedures initiated in USA).

Chronic hepatitis C, more than other forms of hepatitis, can beassociated with extrahepatic manifestations associated with the presenceof HCV such as porphyria cutanea tarda, cryoglobulinemia (a form ofsmall-vessel vasculitis) and glomerulonephritis (inflammation of thekidney), specifically membranoproliferative glomerulonephritis (MPGN).Hepatitis C is also rarely associated with sicca syndrome (an autoimmunedisorder), thrombocytopenia, lichen planus, diabetes mellitus and withB-cell lymphoproliferative disorders.

Compounds which have been shown to be useful in the treatment and/orinhibition of HCV infections and which may be combined with2′-fluoronucleoside compounds according to the present invention for thetreatment of HCV infections include, for example, NM 283, ribavirin,VX-950 (telaprevir), SCH 50304, TMC435, VX-500, BX-813, SCH503034,R1626, ITMN-191 (R7227), R7128, PF-868554, TT033, CGH-759, GI 5005,MK-7009, SIRNA-034, MK-0608, A-837093, GS 9190, ACH-1095, GSK625433,TG4040 (MVA-HCV), A-831, F351, NS5A, NS4B, ANA598, A-689, GNI-104,IDX102, ADX184, GL59728, GL60667, PSI-7851, TLR9 Agonist, PHX1766, SP-30and mixtures thereof, and other antiviral compounds as identifiedherein.

The term “Herpes simplex virus”, “Herpes simplex virus-1” (HSV-1),“Herpes simplex virus-2” (HSV-2), are two species of the herpes virusfamily, Herpesviridae, which cause infections in humans. As with otherherpesviridae, herpes simplex virus may produce life-long infections.They are also called Human Herpes Virus 1 and 2 (HHV-1 and HHV-2) andare neurotropic and neuroinvasive viruses; they enter and hide in thehuman nervous system, accounting for their durability in the human body.HSV-1 is commonly associated with herpes outbreaks of the face known ascold sores or fever blisters, whereas HSV-2 is more often associatedwith genital herpes, although each of the two strains of HSV may befound in areas normally associated with the other strain.

An infection by a herpes simplex virus is marked by watery blisters inthe skin or mucous membranes of the mouth, lips or genitals. Lesionsheal with a scab characteristic of herpetic disease. However, theinfection is persistent and symptoms may recur periodically as outbreaksof sores near the site of original infection. After the initial, orprimary, infection, HSV becomes latent in the cell bodies of nerves inthe area. Some infected people experience sporadic episodes of viralreactivation, followed by transportation of the virus via the nerve'saxon to the skin, where virus replication and shedding occurs. Herpes iscontagious if the carrier is producing and shedding the virus. This isespecially likely during an outbreak but possible at other times. Thereis no cure yet, but there are treatments which reduce the likelihood ofviral shedding.

The terms “cytomegalovirus”, “CMV” human cytomegalovirus, “HCMV” areused to describe a herpes viral genus of the Herpesviruses group: inhumans it is also commonly known as HCMV or Human Herpesvirus 5 (HHV-5).CMV belongs to the Betaherpesvirinae subfamily of Herpesviridae, whichalso includes Roseolovirus. Other herpesviruses fall into thesubfamilies of Alphaherpesvirinae (including HSV 1 and 2 and varicella)or Gammaherpesvirinae (including Epstein-Barr virus).^([1]) Allherpesviruses share a characteristic ability to remain latent within thebody over long periods.

HCMV infections are frequently associated with salivary glands, thoughthey may be found throughout the body. HCMV infection can also be lifethreatening for patients who are immunocompromised (e.g. patients withHIV, organ transplant recipients, or neonates).^([1]) Other CMV virusesare found in several mammal species, but species isolated from animalsdiffer from HCMV in terms of genomic structure, and have not beenreported to cause human disease.

HCMV is found throughout all geographic locations and socioeconomicgroups, and infects between 50% and 80% of adults in the United States(40% worldwide) as indicated by the presence of antibodies in much ofthe general population. Seroprevalence is age-dependent: 58.9% ofindividuals aged 6 and older are infected with CMV while 90.8% ofindividuals aged 80 and older are positive for HCMV. HCMV is also thevirus most frequently transmitted to a developing fetus. HCMV infectionis more widespread in developing countries and in communities with lowersocioeconomic status and represents the most significant viral cause ofbirth defects in industrialized countries.

Most healthy people who are infected by HCMV after birth have nosymptoms. Some of them develop an infectious mononucleosis/glandularfever-like syndrome, with prolonged fever, and a mild hepatitis. A sorethroat is common. After infection, the virus remains latent in the bodyfor the rest of the person's life. Overt disease rarely occurs unlessimmunity is suppressed either by drugs, infection or old-age. InitialHCMV infection, which often is asymptomatic is followed by a prolonged,inapparent infection during which the virus resides in cells withoutcausing detectable damage or clinical illness.

Infectious CMV may be shed in the bodily fluids of any infected person,and can be found in urine, saliva, blood, tears, semen, and breast milk.The shedding of virus can occur intermittently, without any detectablesigns or symptoms.

The term “Varicella Zoster virus” or “VZV” is used to describe one ofeight herpes viruses known to infect humans (and other vertebrates). VZVcommonly causes chicken-pox in children and both shingles andpostherpetic neuralgia in adults. Varicella-zoster virus is known bymany names, including: chickenpox virus, varicella virus, zoster virus,and human herpes virus type 3 (HHV-3). Primary VZV infection results inchickenpox (varicella), which may rarely result in complicationsincluding encephalitis or pneumonia. Even when clinical symptoms ofchickenpox have resolved, VZV remains dormant in the nervous system ofthe infected person (virus latency), in the trigeminal and dorsal rootganglia. In about 10-20% of cases, VZV reactivates later in lifeproducing a disease known as herpes zoster or shingles. Seriouscomplications of shingles include postherpetic neuralgia, zostermultiplex, myelitis, herpes ophthalmicus, or zoster sine herpete.

VZV is closely related to the herpes simplex viruses (HSV), sharing muchgenome homology. Many of the known envelope glycoproteins of VZVcorrespond with those in HSV. VZV, unlike HSV, fails to produce the LAT(latency-associated transcripts) that play an important role inestablishing HSV latency (herpes simplex virus). The virus is verysusceptible to disinfectants, notably sodium hypochlorite. Within thehuman body, along with compounds of the present invention, it can be,treated by a number of drugs and therapeutic agents including acyclovir,zoster-immune globulin (ZIG), and vidarabine.

The term “Epstein Barr virus” or “EBV”, also called Human herpesvirus 4(HHV-4), is a virus of the herpes family and is one of the most commonviruses in humans. Most people become infected with EBV, which is oftenasymptomatic, but infection commonly causes infectious mononucleosis(also known as glandular fever). Epstein-Barr virus occurs worldwide.Most people become infected with EBV sometime during their lives, andtherefore gain adaptive immunity, preventing repeated sickness fromre-infection through EBV antibodies. In the United States, as many as95% of adults between 35 and 40 years of age have been infected. Infantsbecome susceptible to EBV as soon as maternal antibody protection(present at birth) disappears. When infection with EBV occurs duringadolescence or young adulthood, it causes infectious mononucleosis 35%to 69% of the time.

The term “neoplasia” or “cancer” is used throughout the specification torefer to the pathological process that results in the formation andgrowth of a cancerous or malignant neoplasm, i.e., abnormal tissue thatgrows by cellular proliferation, often more rapidly than normal andcontinues to grow after the stimuli that initiated the new growth cease.Malignant neoplasms show partial or complete lack of structuralorganization and functional coordination with the normal tissue and mostinvade surrounding tissues, metastasize to several sites, and are likelyto recur after attempted removal and to cause the death of the patientunless adequately treated. As used herein, the term neoplasia is used todescribe all cancerous disease states and embraces or encompasses thepathological process associated with malignant hematogenous, ascitic andsolid tumors. Representative cancers include; for example, stomach,colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpusuteri, ovary, prostate, testis, bladder, renal, brain/CNS, head andneck, throat, Hodgkin's disease, non-Hodgkin's lymphoma, multiplemyeloma, leukemia, melanoma, acute lymphocytic leukemia, acutemyelogenous leukemia, Ewing's sarcoma, small cell lung cancer,choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairycell leukemia, mouth/pharynx, nasopharyngeal, oesophagus, larynx, kidneycancer and lymphoma, among others, which may be treated by one or morecompounds according to the present invention. In certain aspects of theinvention, the term tumor or cancer refers to hepatocellular cancer,lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma and nasopharyngealcancer, which are cancers which frequently occur secondary to hepatitisB virus (HBV), hepatitis C virus (HCV) and/or Epstein-Barr virus (EBV)infections.

The term “tumor” is used to describe a malignant or benign growth ortumefacent.

The term “anti-cancer compound” or “anti-cancer agent” is used todescribe any compound which may be used to treat cancer. Anti-cancercompounds for use in the present invention may be co-administered withone or more of the compounds according to the present invention to treatcancer which occurs in the presence of a viral infection or secondary toa viral infection. Exemplary anti-cancer compounds for use in thepresent invention for co-administration with compounds according to thepresent invention include a number of compounds which are broadlycharacterized as antimetabolites, inhibitors of topoisomerase I and II,alkylating agents and microtubule inhibitors (e.g., taxol). Anti-cancercompounds for use in the present invention include, for example,Aldesleukin; Alemtuzumab; alitretinoin; allopurinol; altretamine;amifostine; anastrozole; arsenic trioxide; Asparaginase; BCG Live;bexarotene capsules; bexarotene gel; bleomycin; busulfan intravenous;busulfan oral; calusterone; capecitabine; carboplatin; carmustine;carmustine with Polifeprosan 20 Implant; celecoxib; chlorambucil;cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabineliposomal; dacarbazine; dactinomycin; actinomycin D; Darbepoetin alfa;daunorubicin liposomal; daunorubicin, daunomycin; Denileukin diftitox,dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal;Dromostanolone propionate; Elliott's B Solution; epirubicin; Epoetinalfa estramustine; etoposide phosphate; etoposide (VP-16); exemestane;Filgrastim; floxuridine (intraarterial); fludarabine; fluorouracil(5-FU); fulvestrant; gemtuzumab ozogamicin; goserelin acetate;hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinibmesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan; letrozole;leucovorin; levamisole; lomustine (CCNU); meclorethamine (nitrogenmustard); megestrol acetate; melphalan (L-PAM); mercaptopurine (6-MP);mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone;nandrolone phenpropionate; Nofetumomab; LOddC; Oprelvekin; oxaliplatin;paclitaxel; pamidronate; pegademase; Pegaspargase; Pegfilgrastim;pentostatin; pipobroman; plicamycin; mithramycin; porfimer sodium;procarbazine; quinacrine; Rasburicase; Rituximab; Sargramostim;streptozocin; talbuvidine (LDT); talc; tamoxifen; temozolomide;teniposide (VM-26); testolactone; thioguanine (6-TG); thiotepa;topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin (ATRA);Uracil Mustard; valrubicin; valtorcitabine (monoval LDC); vinblastine;vinorelbine; zoledronate; and mixtures thereof, among others.

The term “pharmaceutically acceptable salt” is used throughout thespecification to describe, where applicable, a salt form of one or moreof the compounds described herein which are presented to increase thesolubility of the compound in the gastic juices of the patient'sgastrointestinal tract in order to promote dissolution and thebioavailability of the compounds. Pharmaceutically acceptable saltsinclude those derived from pharmaceutically acceptable inorganic ororganic bases and acids, where applicable. Suitable salts include thosederived from alkali metals such as potassium and, sodium, alkaline earthmetals such as calcium, magnesium and ammonium salts, among numerousother acids well known in the pharmaceutical art. Sodium and potassiumsalts are particularly preferred as neutralization salts of thephosphates according to the present invention.

The term “pharmaceutically acceptable derivative” is used throughout thespecification to describe any pharmaceutically acceptable prodrug form(such as an ester, ether or amide or other prodrug group) which, uponadministration to a patient, provides directly or indirectly the presentcompound or an active metabolite of the present compound.

The term “alkyl” shall mean within its context a C₁-C₂₀, preferably aC₁-C₁₀ linear, branch-chained or cyclic fully saturated hydrocarbonradical, which may be optionally substituted. It is noted that in theevent that a carbon range is provided, that range signifies that eachand every carbon is considered part of the range. For example a C₁-C₂₀group describes a group with a single carbon, two carbon atoms, threecarbon atoms, four carbon atoms, etc. The term “ether” shall mean anoptionally substituted C₁ to C₂₀ ether group, formed from an oxygen andan alkyl group, or alternatively, may also contain at least one oxygenwithin the alkyl or alkylene chain.

The term “aromatic” or “aryl” shall mean within its context asubstituted or unsubstituted monovalent carbocyclic aromatic radicalhaving a single ring (e.g., phenyl) or multiple condensed rings (e.g.,naphthyl, anthracene, phenanthrene). Other examples include optionallysubstituted heterocyclic aromatic ring groups (“heteroaromatic” or“heteroaryl”) having one or more nitrogen, oxygen, or sulfur atoms inthe ring, and preferably include five or six-membered heteroaryl groups,such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine,pyrazine, triazole, oxazole, among others, but can also include fusedring heteroaryl groups such as indole groups, among others. Thepreferred aryl group in compounds according to the present invention isa phenyl or a substituted phenyl group.

The term “heterocycle” shall mean an optionally substituted moiety whichis cyclic and contains at least one atom other than a carbon atom, suchas a nitrogen, sulfur, oxygen or other atom, which ring may be saturatedand/or unsaturated.

The term “unsubstituted” shall mean substituted only with hydrogenatoms. The term “substituted” shall mean, within the chemical context ofthe compound defined, a substituent (each of which substituent mayitself be substituted) selected from a hydrocarbyl (which may besubstituted itself, preferably with an optionally substituted alkyl orfluoro group, among others), preferably an alkyl (generally, no greaterthan about 3 carbon units in length), including CF₃, an optionallysubstituted aryl, halogen (F, Cl, Br, I), thiol, hydroxyl, carboxyl,C₁-C₃ alkoxy, alkoxycarbonyl, CN, nitro or an optionally substitutedamine (e.g. an alkyleneamine or a C₁-C₃ monoalkyl or dialkyl amine).Various optionally substituted moieties may be substituted with 3 ormore substituents, preferably no more than 3 substituents and preferablywith 1 or 2 substituents.

The term “acyl” is used throughout the specification to describe a groupat the 5′ or 3′ position of the nucleoside analog (i.e., at the freehydroxyl position in the carbocyclic moiety) or on the exocyclic amineof the nucleoside base which contains a C₁ to C₂₀ linear, branched orcyclic alkyl chain. The acyl group in combination with the hydroxylgroup results in an ester and the acyl group in combination with anexocyclic amine group results in an amide, which, after administration,may be cleaved to produce the free nucleoside form of the presentinvention. Acyl groups according to the present invention arerepresented by the structure:

where R⁴ is a C₁ to C₂₀ linear, branched or cyclic, alkyl group which isoptionally substituted preferably with, for example, 1-3 hydroxylgroups, 1-3 halo groups (F, Cl, Br, I) or an amine group (which itselfmay be optionally substituted with one or two C₁-C₆ alkyl groupsoptionally bearing between 1 and 3 hydroxyl groups), alkoxyalkyl(including an ethylene oxide chain which may end in a free hydroxylgroup or a C₁-C₁₀ alkyl group and ranges in molecular weight from about50 to about 40,000 or about 200 to about 5,000), such as phenoxymethyl,aryl, alkoxy, alkoxycarbonyloxy groups (e.g.,[(isopropoxycarbonyl)oxy]-methoxy), aryloxyalkyl, among others, all ofwhich groups may be optionally substituted, as described above.Preferred acyl groups are those where R⁴ is a C₁ to C₁₂ alkyl group.Acyl groups according to the present invention also include, forexample, those acyl groups derived from benzoic acid and related acids,3-chlorobenzoic acid, succinic, capric and caproic, lauric, myristic,palmitic, stearic and oleic groups, among numerous others and mayinclude such related groups as sulfone groups such as mesylate groups.All groups may be appropriatedly substituted within context as otherwisedescribed herein. One of ordinary skill in the art will recognize theacyl groups which will have utility in the present invention, either tosynthesize the target pharmaceutical compounds or as prodrug of thenucleosides according to the present invention.

The term “amino acid” or “amino acid residue” shall mean, withincontext, a radical of a D- or L-amino acid which is covalently bound toa nucleoside analog at the 4′ exocyclic amine position of the cytosinebase or the 5′- or 3′-OH position of the sugar synthon (R², R¹ orR^(1a)) through a carboxylic acid moiety of the amino acid, thus formingrespectively, an amide or ester group linking the nucleoside to theamino acid. Amino acids may also be used to provide phosphoamidategroups in nucleoside compounds according to the present invention asotherwise described herein. Representative amino acids include bothnatural and unnatural amino acids, preferably including, for example,alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine,cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine,isoleucine, lysine, leucine, methionine, proline, serine, threonine,valine, tryptophan or tyrosine, among others.

The term “phosphate ester” or “phosphodiester” (which term includesphosphotriester groups and phosphoamidate groups in context) is usedthroughout the specification to describe mono-phosphate groups at the 5′position of the carboyclic sugar synthon which are mono- or diesterified(or amidated and optionally esterified in the case of a phosphoamidate)such that the phosphate group is negatively charged or is renderedneutral, i.e., has a neutral charge. Phosphate esters, phosphodiestersand/or phosphoamidate groups for use in the present invention includethose represented by the structures:

where each R⁵ and R⁶ is independently selected from H, a C₁ to C₂₀linear, branched or cyclic alkyl group, alkoxyalkyl, aryloxyalkyl, suchas phenoxymethyl, optionally substituted aryl (especially an optionallysubstituted phenyl group) and alkoxy, among others, includingalkoxycarbonyloxy groups (e.g., (isopropoxycarbonyl)oxy]-methoxy) eachof which groups may be optionally substituted (e.g., a phenyl or othergroup may be optionally substituted as otherwise described herein orpreferably with from one to three, C₁-C₆ alkyl groups, halogen,preferably F, Cl or Br, nitro, cyano, or C₂-C₆ carboxyester groups) withthe proviso that at least one R⁵ group is other than H, or the two R⁵groups together form a five- or six-membered heterocyclic group;B′ is a

group or a group obtained from an amino acid (a natural or unnaturalamino acid such as, for example, alanine, β-alanine, arginine,asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine,glycine, phenylalanine, histidine, isoleucine, lysine, leucine,methionine, proline, serine, threonine, valine, tryptophan or tyrosine,among others) to preferably provide a group according to the structure

Where i is 0, 1, 2 or 3 (preferably 0)R⁷ is a C₁ to C₂₀ linear, branched or cyclic alkyl or acyl group,alkoxyalkyl, aryloxyalkyl, such as phenoxymethyl, optionally substitutedaryl group (as described above) and alkoxy, among others, each of whichgroups may be optionally substituted;R⁸ is sidechain of an amino acid, preferably a sidechain of an aminoacid selected from the group consisting of alanine, β-alanine, arginine,asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine,glycine, phenylalanine, histidine, isoleucine, lysine, leucine,methionine, proline, serine, threonine, valine, tryptophan or tyrosine(preferably R⁸ is derived from alanine, leucine, isoleucine orthreonine, more preferably alanine-R⁸ is methyl), and R″ is a C₁ to C₂₀linear, branched or cyclic alkyl or a phenyl or heteroaryl group, eachof which groups is optionally substituted.

Preferred monophosphate esters for use in prodrug forms according to thepresent invention are those where R⁵ is a C₁ to C₂₀ linear or branchedchain alkyl group, more preferably a C₁ to C₃ alkyl group, all of whichgroups may be optionally substituted. Other compounds which arepreferred are as otherwise set forth herein, especially, where R¹ is aphosphoamidate group as otherwise described herein. A preferredphosphoamidate is

Where R_(p1) is an optionally substituted (OH, halo) C₁-C₂₀ alkyl group,preferably a C₁-C₄ alkyl group, even more preferably a methyl, ethyl,isopropyl group or isobutyl group; andR^(P) is H, nitro, cyano, methoxy, or a C₁-C₃ alkyl group optionallysubstituted with from 1-3 halogen substituents (preferably F).

Preferred phosphoamidate groups for R¹ include those according to thechemical structure:

Where R^(P) is H or C₁-C₃ alkyl group (preferably H) and R_(N) ismethyl, ethyl, isopropyl or isobutyl group, more preferably a methyl orisopropyl group,In other embodiments R¹ is a

group.

The term “effective amount” shall mean an amount or concentration of acompound according to the present invention which is effective withinthe context of its administration or use, which may be inhibitory,prophylactic and/or therapeutic. Within context, all active compoundswhich are used in the present invention are used in effective amounts.The present compound also relates to combinations of compounds whichcontain effective amounts of each of the compounds used, whether thatcombination is additive or synergistic in effect, provided that theoverall effect of the combination of compounds is to inhibit the growth,reduce the likelihood of or treat viral infections in patients asotherwise described herein.

The term “D-configuration” as used in the context of the presentinvention refers to the configuration of the nucleoside compoundsaccording to the present invention which mimics the naturalconfiguration of sugar moeties as opposed to the unnatural occurringnucleosides or “L” configuration. The term “β” or “β anomer” is used todescribe nucleoside analogs according to the present invention in whichthe nucleoside base is configured (disposed) above the plane of thecarbocyclic moiety in the compound.

The term “enantiomerically enriched” is used throughout thespecification to describe a nucleoside which includes at least about95%, preferably at least about 96%, more preferably at least about 97%,even more preferably, at least about 98%, and even more preferably atleast about 100% or more of a single enantiomer of that nucleoside.Carbocyclic nucleoside compounds according to the present invention aregenerally β-D-nucleoside compounds. When the present compounds accordingto the present invention are referred to in this specification, it ispresumed that the nucleosides have the D-nucleoside configuration andare enantiomerically enriched (preferably, about 100% of theD-nucleoside), unless otherwise stated. The term “diasteromericallypure” is used to describe a single diastereomer of a compound accordingto the present invention which contains at least 95%, 96%, 97%, 98%,99%, 99.5% or 100% by weight of a single diastereomer to the enclusionof other possible diastereomers.

The terms “coadminister” and “coadministration” are used synonymously todescribe the administration of at least one of the nucleoside compoundsaccording to the present invention in combination with at least oneother agent, preferably at least one additional anti-viral agent,including other nucleoside anti-viral agents which are specificallydisclosed herein in amounts or at concentrations which would beconsidered to be effective amounts at or about the same time. While itis preferred that coadministered agents be administered at the sametime, agents may be administered at times such that effectiveconcentrations of both (or more) agents appear in the patient at thesame time for at least a brief period of time. Alternatively, in certainaspects of the present invention, it may be possible to have eachcoadministered agent exhibit its inhibitory effect at different times inthe patient, with the ultimate result being the inhibition of the virusand the treatment of the aforementioned infections. Of course, when morethan one viral or other infection or other condition is present, thepresent compounds may be combined with agents to treat that otherinfection or condition as required. In certain preferred compositionsand methods, the present carbocyclic nucleoside compounds arecoformulated and/or coadministered with at least one additionalantiviral agent, preferably wherein the antiviral agent is acyclovir,famciclovir, ganciclovir, valaciclovir, vidaribine, ribavirin,zoster-immune globulin (ZIG), lamivudine, adefovir dipivoxil, entecavir,telbivudine, clevudine, tenofovir or a mixture thereof. In the case ofHBV infections, the present 2′-fluorocarbocyclic nucleoside compoundsmay be coadministered preferably with another anti-HBV agent for exampleHepsera (adefovir dipivoxil), lamivudine, entecavir, telbivudine,tenofovir, emtricitabine, clevudine, valtoricitabine, amdoxovir,pradefovir, racivir, BAM 205, nitazoxanide, UT 231-B, Bay 41-4109,EHT899, zadaxin (thymosin alpha-1) and mixtures thereof. In the case ofHCV infections, the present 2′-fluorocarbocyclic nucleoside compoundsmay be coadministered preferably with another anti-HCV agent forexample, NM 283, ribavirin, VX-950 (telaprevir), SCH 50304, TMC435,VX-500, BX-813, SCH503034, R1626, ITMN-191 (R7227), R7128, PF-868554,TT033, CGH-759, GI 5005, MK-7009, SIRNA-034, MK-0608, A-837093, GS 9190,ACH-1095, GSK625433, TG4040 (MVA-HCV), A-831, F351, NS5A, NS4B, ANA598,A-689, GNI-104, IDX102, ADX184, GL59728, GL60667, PSI-7851, TLR9Agonist, PHX1766, SP-30 and mixtures thereof.

In alternative embodiments, especially in the case of HBV, HCV orEpstein-Barr treatment, compounds according to the present invention mayalso be coadministered with an anticancer agent.

The term “independently” is used herein to indicate that the variable,which is independently applied, varies independently from application toapplication.

The present invention relates to carbocyclic nucleoside compoundsaccording to the structure:

Where B is

Wherein R is H, F, Cl, Br, I, C₁-C₄ alkyl (preferably CH₃), —C≡N,—C≡C—R_(a),

X is H, C₁-C₄ alkyl (preferably, CH₃), F, Cl, Br or I;R_(a) is H or a —C₁-C₄ alkyl group;R¹ and R^(1a) are each independently, H, an acyl group, a C₁-C₂₀ alkylor ether group, an amino acid residue (D or L), a phosphate,diphosphate, triphosphate, phosphodiester or phosphoamidate group ortogether R¹ and R^(1a) form a carbodiester, phosphodiester orphosphoamidate group with the oxygen atoms to which they are bonded;R² is H, an acyl group, a C₁-C₂₀ alkyl or ether group or an amino acidresidue (D or L);Or a pharmaceutically acceptable salt, enantiomer, hydrate or solvatethererof.

Preferably R^(1a) is H. Also preferably, R¹ and R² are eachindependently H or a C₂-C₂₀ acyl group, more preferably H. In otherembodiments, R¹ is a phosphoamidate group as otherwise described hereinor a phosphoamidate group according to the structure:

Where R_(p1) is an optionally substituted (OH, halo) C₁-C₂₀ alkyl group,preferably a C₁-C₄ alkyl group, even more preferably a methyl, ethyl,isopropyl group or isobutyl group; andR^(P) is H, nitro, cyano, methoxy, or a C₁-C₃ alkyl group optionallysubstituted with from 1-3 halogen substituents (preferably F).

Preferred phosphoamidate groups for R¹ include those according to thechemical structure:

Where R_(p1) is methyl, ethyl, isopropyl or isobutyl andR^(P) is H, nitro, cyano, methoxy or C₁-C₃ alkyl, preferably H. Incertain aspects of the invention the R¹ phosphoamidate group ispreferably a

When R¹ is a phosphoamidate group as described above, R^(1a) ispreferably H and R² is preferably H or a C₂-C₂₀ acyl group.

-   -   B is preferably

In alternative preferred aspects, the compound is represented by thechemical structure:

Where B is as described above, is preferably

and R¹, R^(1a) and R² are as otherwise described hereinabove, mostpreferably, R^(1a) and R² are H and R¹ is preferably a phosphoamidategroup, especially including a phosphoamidate group according to thestructure:

Where R_(p1) is methyl, ethyl, isopropyl or isobutyl andR^(p) is H.

The present invention also relates to pharmaceutical compositionscomprising an effective amount of a compound as described above,optionally in combination with a pharmaceutically acceptable carrier,additive or excipient. In alternative embodiments, pharmaceuticalcompositions may also contain one or more additional antiviral agents asotherwise described herein in combination with a additive, carrier orexcipient.

Methods of treatment represent further embodiments according to thepresent invention. In this aspect, a method of treating or reducing thelikelihood of a viral infection or a secondary disease state orcondition thereof, in particular, a viral infection from HBV, HCV,HSV-1, HSV-2, CMV (including HCMV), VZV or EBV infection in a patient inneed of therapy or at risk for infection or a secondary disease state orcondition thereof comprises administering to said an effective amount ofa compound as otherwise described above. Alternative embodiments rely oncoadministering compounds according to the present invention incombination with additional antiviral agents to said patient. Inpreferred aspects, a method of treating or reducing the likelihood ofHBV, including a drug resistant strain thereof or a secondary disease orcondition which occurs as a consequence of HBV is directed toadministering to a patient in need an effective amount of compoundaccording to the present invention as described herein, preferably acompound according to the chemical structure:

Or a pharmaceutically acceptable salt, solvate or polymorph thereof.

Pharmaceutical compositions based upon the nucleoside compoundsaccording to the present invention comprise one or more of theabove-described compounds in an effective amount for treating orreducing the likelihood of a viral infection, especially a HBV, HCV,HSV-1, HSV-2, CMV (HMCV), VZV or EBV infection in a patient in need oftherapy thereof, optionally in combination with a pharmaceuticallyacceptable additive, carrier or excipient. One of ordinary skill in theart will recognize that a therapeutically effective amount will varywith the infection or condition to be treated, its severity, thetreatment regimen to be employed, the pharmacokinetics of the agentused, as well as the patient or subject (animal or human) to be treated.

In the pharmaceutical aspect according to the present invention, thecompound according to the present invention is formulated preferably inadmixture with a pharmaceutically acceptable carrier. In general, it ispreferable to administer the pharmaceutical composition inorally-administrable form, but certain formulations may be administeredvia a parenteral, intravenous, intramuscular, transdermal, buccal,subcutaneous, suppository or other route. Intravenous and intramuscularformulations are preferably administered in sterile saline. In certaininstances, transdermal administration may be preferred. Of course, oneof ordinary skill in the art may modify the formulations within theteachings of the specification to provide numerous formulations for aparticular route of administration without rendering the compositions ofthe present invention unstable or compromising their therapeuticactivity. In particular, the modification of the present compounds torender them more soluble in water or other vehicle, for example, may beeasily accomplished by minor modifications (salt formulation,esterification, etc.) which are well within the ordinary skill in theart. It is also well within the routineer's skill to modify the route ofadministration and dosage regimen of a particular compound in order tomanage the pharmacokinetics of the present compounds for maximumbeneficial effect in patients.

In certain pharmaceutical dosage forms, the pro-drug form of thecompounds, especially including acylated (acetylated or other) and ether(alkyl and related) derivatives, phosphate esters and various salt formsof the present compounds, are preferred. One of ordinary skill in theart will recognize how to readily modify the present compounds topro-drug forms to facilitate delivery of active compounds to a targetedsite within the host organism or patient. The routineer also will takeadvantage of favorable pharmacokinetic parameters of the pro-drug forms,where applicable, in delivering the present compounds to a targeted sitewithin the host organism or patient to maximize the intended effect ofthe compound.

The amount of compound included within active formulations according tothe present invention is an effective amount for treating the infectionor condition, especially a viral infection as otherwise describedherein. In general, a therapeutically effective amount of the presentcompound in pharmaceutical dosage form usually ranges from about 0.05mg/kg to about 100 mg/kg per day or more, more preferably, slightly lessthan about 1 mg/kg to about 25 mg/kg per day of the patient orconsiderably more, depending upon the compound used, the condition orinfection treated and the route of administration. The active nucleosidecompound according to the present invention is preferably administeredin amounts ranging from about 0.5 mg/kg to about 25 mg/kg per day of thepatient, depending upon the pharmacokinetics of the agent in thepatient. This dosage range generally produces effective blood levelconcentrations of active compound which may range from about 0.05 toabout 100 micrograms/cc of blood in the patient. For purposes of thepresent invention, a prophylactically or preventive effective amount(i.e. an amount which is effective to reduce the likelihood of a patientat risk from contracting a viral infection) of the compositionsaccording to the present invention falls within the same concentrationrange as set forth above for therapeutically effective amount and isusually the same as a therapeutically effective amount.

Administration of the active compound may range from continuous(intravenous drip) to several oral administrations per day (for example,Q.I.D.) or transdermal administration and may include oral; topical,parenteral, intramuscular, intravenous, sub-cutaneous, transdermal(which may include a penetration enhancement agent), buccal andsuppository administration, among other routes of administration.Enteric coated oral tablets may also be used to enhance bioavailabilityof the compounds from an oral route of administration. The mosteffective dosage form will depend upon thebioavailability/pharmacokinetics of the particular agent chosen as wellas the severity of disease in the patient. Oral dosage forms areparticularly preferred, because of ease of administration andprospective favorable patient compliance.

To prepare the pharmaceutical compositions according to the presentinvention, a therapeutically effective amount of one or more of thecompounds according to the present invention is preferably intimatelyadmixed with a pharmaceutically acceptable carrier according toconventional pharmaceutical compounding techniques to produce a dose. Acarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral. Inpreparing pharmaceutical compositions in oral dosage form, any of theusual pharmaceutical media may be used. Thus, for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives including water, glycols, oils, alcohols,flavouring agents, preservatives, colouring agents and the like may beused. For solid oral preparations such as powders, tablets, capsules,and for solid preparations such as suppositories, suitable carriers andadditives including starches, sugar carriers, such as dextrose,mannitol, lactose and related carriers, diluents, granulating agents,lubricants, binders, disintegrating agents and the like may be used. Ifdesired, the tablets or capsules may be enteric-coated or sustainedrelease by standard techniques. The use of these dosage forms maysignificantly enhance the bioavailability of the compounds in thepatient.

For parenteral formulations, the carrier will usually comprise sterilewater or aqueous sodium chloride solution, though other ingredients,including those which aid dispersion, also may be included. Of course,where sterile water is to be used and maintained as sterile, thecompositions and carriers must also be sterilized. Injectablesuspensions may also be prepared, in which case appropriate liquidcarriers, suspending agents and the like may be employed.

Liposomal suspensions (including liposomes targeted to viral antigens)may also be prepared by conventional methods to produce pharmaceuticallyacceptable carriers. This may be appropriate for the delivery of freenucleosides, acyl/alkyl nucleosides or phosphate ester pro-drug forms ofthe nucleoside compounds according to the present invention.

In particularly preferred embodiments according to the presentinvention, the compounds and compositions are used to treat, prevent ordelay the onset of a viral infection as otherwise disclosed herein (HBV,HCV, HSV-1, HSV-2, CMV, VZV and/or EBV). Preferably, to treat, preventor delay the onset of these infections or disease states and/orconditions which occur secondary to these viral infections (especiallycirrhosis, fibrosis and/or liver cancer secondary to HBV and/or HCVinfections), the compositions will be administered in oral dosage formin amounts ranging from about 250 micrograms up to about 500 mg or moreat least once a day, preferably, up to four times a day. The presentcompounds are preferably administered orally, but may be administeredparenterally, topically or in suppository form.

In the case of the co-administration of the present compounds incombination with an another compound used to treat a viral infection, inparticular, a viral infection such as a HBV, HCV, HSV-1, HSV-2, CMV, VZVand/or EBV infection, the amount of the carbocyclic nucleoside compoundaccording to the present to be administered ranges from about 1 mg/kg.of the patient to about 500 mg/kg. or more of the patient orconsiderably more, depending upon the second agent to be co-administeredand its potency against each of the viral infections to be inhibited,the condition or infection treated and the route of administration. Inthe case of coadministration, the other antiviral agent may bepreferably administered in amounts ranging from about 100 ug/kg(micrograms per kilogram) to about 500 mg/kg. In certain preferredembodiments, these compounds may be preferably administered in an amountranging from about 1 mg/kg to about 50 mg/kg or more (usually up toabout 100 mg/kg), generally depending upon the pharmacokinetics of thetwo agents in the patient. These dosage ranges generally produceeffective blood level concentrations of active compound in the patient.Typical antiviral agents which may be coadministered with compoundsaccording to the present invention include acyclovir, famciclovir,ganciclovir, valaciclovir, vidaribine, ribavirin, zoster-immune globulin(ZIG), lamivudine, adefovir dipivoxil, entecavir, telbivudine,clevudine, tenofovir and mixtures thereof. In the case of treating HBVinfections, preferred compounds for combining with the presentT-fluorocarbocyclic nucleoside compounds include, for example, Hepsera(adefovir dipivoxil), lamivudine, entecavir, telbivudine, tenofovir,emtricitabine, clevudine, valtoricitabine, amdoxovir, pradefovir,racivir, BAM 205, nitazoxanide, UT 231-B, Bay 41-4109, EHT899, zadaxin(thymosin alpha-1) and mixtures thereof. In the case of HCV infections,the present 2′-fluorocarbocyclic nucleoside compounds may becoadministered preferably with another anti-HCV agent for example, NM283, VX-950 (telaprevir), SCH 50304, TMC435, VX-500, BX-813, SCH503034,R1626, ITMN-191 (R7227), R7128, PF-868554, TT033, CGH-759, GI 5005,MK-7009, SIRNA-034, MK-0608, A-837093, GS 9190, ACH-1095, GSK625433,TG4040 (MVA-HCV), A-831, F351, NS5A, NS4B, ANA598, A-689, GNI-104,IDX102, ADX184, GL59728, GL60667, PSI-7851, TLR9 Agonist, PHX1766, SP-30and mixtures thereof.

The compounds according to the present invention, may advantageously beemployed prophylactically to prevent or reduce the likelihood of a viralinfection or to prevent or reduce the likelihood of the occurrence ofclinical symptoms associated with the viral infection or to prevent orreduce the likelihood of the spread of a viral infection to anotherperson. Thus, the present invention also encompasses methods for theprophylactic treatment of a HBV, HCV, HSV-1, HSV-2, CMV, VZV and/or EBVinfection. In this aspect according to the present invention, thepresent compositions may be used to prevent, reduce the likelihood ofand/or delay the onset of a viral infection or a virus related diseasestate or condition (e.g., cirrhosis, fibrosis and/or liver cancer) orthe spread of infection to other people. This prophylactic methodcomprises administering to a patient in need of such treatment or who isat risk for the development of a HBV, HCV, HSV-1, HSV-2, CMV, VZV and/orEBV infection, including a virus related disease state or condition oran infected patient who wishes to prevent or reduce the likelihood of aviral infection from spreading to another person, an amount of acompound according to the present invention alone or in combination withanother anti-viral effective for alleviating, preventing or delaying theonset of the viral infection. In the prophylactic treatment according tothe present invention, it is preferred that the antiviral compoundutilized should be as low in toxicity and preferably non-toxic to thepatient. It is particularly preferred in this aspect of the presentinvention that the compound which is used should be maximally effectiveagainst the virus and should exhibit a minimum of toxicity to thepatient. In the case of compounds of the present invention for theprophylactic treatment of viral infections, these compounds may beadministered within the same dosage range for therapeutic treatment(i.e., about 250 micrograms up to about 500 mg. or more from one to fourtimes per day for an oral dosage form) as a prophylactic agent toprevent the proliferation of the viral infection or alternatively, toprolong the onset of or reduce the likelihood of a patient contracting avirus infection which manifests itself in clinical symptoms.

In addition, compounds according to the present invention may beadministered alone or in combination with other agents, including othercompounds of the present invention. Certain compounds according to thepresent invention may be effective for enhancing the biological activityof certain agents according to the present invention by reducing themetabolism, catabolism or inactivation of other compounds and as such,are co-administered for this intended effect.

Chemical Synthesis

In general, compositions according to the present invention aresynthesized readily from D-ribose according to schemes I, II andalternative scheme II, which are presented in attached FIGS. 3, 4, 5 and8. In this scheme, D-ribose is first converted through a series ofchemical steps to a protected carbocyclic five-membered ring as depictedin scheme 1, FIG. 3 (compound 10). Pursuant to scheme I, compound 10 isthen converted to a compound according to the present invention(compound 15/18) by condensing a nucleoside base (in the figure, a6-chloroadenine to produce compound 11, which is subsequently convertedto an amine group as presented to produce compound 15/18. In alternativescheme II (FIG. 5), compound 15/18, is synthesized from compound 10using alternative approaches as outlined in alternative scheme II (FIG.5). Alternative scheme III, FIG. 8 shows that compound 15/18 and itsprodrug 15P containing a phosphoramide group on the 5′position of thesugar synthon Each compound according to the present invention may beproduced by analogy following the general chemical scheme presented inFIGS. 3, 4, 5, 6 and 7.

Each of the carbocyclic nucleoside compounds prepared as above may bereadily converted to prodrug or alternative forms of the presentinvention (e.g., acylated, phosphate or phosphodiester derivatives, etc.as otherwise described herein) utilizing standard synthetic chemistryfor introducing various groups onto the hydroxyl positions at 2′,3′and/or 5′ positions of the carbocyclic moiety or alternatively, at theexocyclic amine position at the 4-position of the cytosine base.Acylation proceeds through well known synthetic methods (acyl anhydride,acyl halide, etc.) and phosphorylation may be performed using standardchemical techniques which are well-known in the art. One of ordinaryskill may readily synthesize compounds according to the presentinvention by utilizing specific chemical steps which are presentedherein or by way of analogy, through the use of chemical steps which arein the literature, by way of analogy.

In the synthesis of carbocyclic nucleosides, the construction of desiredcarbocycles in decent yield and scale is often troublesome. There areonly a few reports aimed at preparation of carbocyclic core with6′-exo-cyclic alkene, including the protocol of the synthesis ofentecavir from Bristol-Meyer Squibb or, through the radical cyclizationreactions.³⁶⁻³⁹ However, these methodologies are not very suitable forthe modification on the 2′-position of the carbo-ring. Recently, theefficient and practical synthetic methodology of the key intermediates 1has been also accomplished by our group.^(33,34,40) Therefore, analternative route (Scheme 1 and 2) has been developed in order toprepare 2′-F-6′-methylene carbocyclic nucleosides.

More specifically, the cyclopentanone 1 was prepared according to theknown procedure.^(33,34,40) Reaction of the enolate of 1 withEschenmoser's salt placed an N,N-dimethylaminomethyl group on theα-position of the ketone. After Hofmann elimination, a 6′-methylene wasinstalled in decent yield. Due to the steric hindrance on the α-face,the α,β-unsaturated ketone 2 was reduced by a typical Luche reductioncondition to give exclusively α-hydroxyl compound 3. Protection ofallylic alcohol by the benzyl group smoothly generated compound 4 in 43%yield from cyclopentanone 1. Simultaneously deprotection of acetonideand tert-butyl groups under acidic condition provided triol 5 in 85%yield. Treatment of triol 5 with dichlorotetraisopropyldisiloxane(TIPDSC1) in pyridine gave a high yield of 3′,5′-diprotected compound 6.The free 2′-α-OH in 6 is ready for a fluorination reaction. Furthermore,when compound 6 was subjected to a three-step protocol includingtriflation, S_(N)2 replacement and deacetylation, 2′-β-OH compound 7 wasobtained in 81% yield, which can be used for the preparation of 2′-α-Fisomers. Reaction of 6 with (diethylamino)sulfur trifiuoride (DAST)yielded a major product as 2′-β-F compound 7. However, subsequentdebenzylation was not successful in the presence of silyl group undereither Birch reduction or Lewis's acid conditions. Therefore, the silylgroup was replaced by benzoyl group via standard procedure to provide10. Compound 10 was then subjected to the borontrichloride (BCl₃) at−78° C. and successfully produced the fully elaborated intermediate 11in 89% yield (Scheme 1).

Construction of nucleoside 12 was accomplished by typical Mitsunobuconditions^(33,34) by treating 11 with 6-chloropurine in the presence oftriphenylphosphine and diisopropyl azodicarboxylate in THF at 0° C. toroom temperature for 1 hour. Unfortunately, direct amination of chlorineatom to amino group and simultaneous hydrolysis of benzoyl groups bymethanolic ammonia was unsuccessful. One molecule of HF was eliminatedunder such condition as confirmed by ¹H-NMR and ¹⁹F-NMR. Interestingly,even very mild condition, such as Staudinger reaction, failed to achievethe transformation. It was reasoned that the 6′-methylene groupactivated the 1′-proton to undergo a trans-elimination reaction to forma stable diene. In order to circumvent the effect of 6′-methylene group,a temporal protection is preferred. Dihydroxylation of the exo-cyclicalkene was performed using osmium tetraoxide/NMO to provide a mixture ofdiasteromers 12. As expected, conversion of 12 to the adenine derivative13 went smoothly by reacting with sodium azide followed by H₂-reductionin 62% yield. Several conditions were then studied to regenerate theolefin from diol. The Corey's olefin synthesis by the desulfurization of1,3-dioxolane-2-thiones with1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine is well known due to itsmildness and effectiveness.⁴¹ However, when we applied this condition tocompound 13, only complex reaction mixture was obtained. Another generalmethod by heating 2-methoxy-1,3-dioxolane derivatives in aceticanhydride was also unsuccessful in the present case, which may be due tothe high reaction temperature.⁴² Finally, we adopted the reductiveelimination protocol which was widely used in the synthesis of2′,3′-dideoxy-2′,3′-dihydro nucleosides or 2′,3′-dideoxynucleosides.⁴³⁻⁴⁵ Diol 13 was reacted with 1-bromocarbonyl-1-methylethylacetate at −30° C. to room temperature followed by activated Zn metal inDMF in the presence of catalytic amount of HOAc at room temperature for8 hours. The desired nucleoside 14 with 6′-methylene group was obtainedin 68% yield in two steps. Based on our previous experience, basiccondition would not be compatible with 14 to deblock the benzoyl groups,as 6′-methylene group and 2′-F are present simultaneously in themolecule. Therefore, a reductive cleavage method was applied. Aftertreating, 14 with diisobutyl alumina hydride (DIBAL-H) in CH₂Cl₂ at −78°C. for 30 min, the target adenosine analog 15 was eventually obtained in76% yield (Scheme 2). Assignment of the structures of newly synthesizednucleosides was accomplished by NMR, elemental analysis, high resolutionmass spectroscopy, and UV spectroscopy.

An alternative approach may also be taken to produce compound 15(labeled as compound 18 in alternative scheme II, FIG. 5), the syntheticsteps which are set forth alternative chemical syntheses (FIG. 5) wereused. Several approaches were taken to produce compound 18 (same ascompound 15 of FIG. 4). Compound 10 was condensed with 6-chloropurineunder the standard Mitsunobu condition to give 11 in 76% yield. However,attempted amination of 11 to obtain the corresponding adenine derivative13 by methanolic ammonia was unsuccessful. Only the byproduct 12 wasisolated, which was probably formed by losing HF under basic conditions.It was speculated that the stability of the elimination-product 12, aconjugated diene, is the driving force to promote the side reaction.Therefore, transient protection of exocyclic double bond was required.Compound 11 was hence treated with osmium tetroxide/NMO to provide 14 in41% of yield. This was treated with NaN₃, followed by H₂ reductionresulted in 62% of the adenine derivative 15a. Reductive elimination of15a with 1-bromocarbonyl-1-methylethyl acetate followed by activated Znin the presence of catalytic amounts of AcOH furnished the desirednucleoside 13 in 68% yield.

Due to the multiple step synthesis as well as low yield of 13 in theroute-1, recently the inventors revised the synthesis to the route-2.N-Boc protected adenine 16 was synthesized according to the reportedprotocol in literature¹⁵ and condensed with 10 to obtain 17 in 76%yield. The deprotection of the Boc group was carried out by TFA toafford 82% of 13. Eventually, the treatment of 13 with DIBAL-H gave thetarget compound 18 (compound 15) in 76% yield. Analytical data forcompound 15/18 is presented in the examples section below.

FIG. 6 provides another depiction of the synthesis of compounds 15/18.In the scheme set forth in FIG. 6, the synthesis of target compound15/18 commenced with ketone 1 as the key intermediate as brieflydescribed in the FIG. 6 scheme. Starting from D-ribose, the ketone 1 wassynthesized via nine steps according to the know procedure of Jin, etal., J. Org. Chem., 68: 9012-9018 (2003). The exocyclic methylene groupwas introduced with Mannich base (Eshenmoser's salt) followed by theHoffmann degradation to an enone, which was selectively reduced by usingsodium borohydride to exclusively give the α-hydroxyl compound 3 in goodyield. The compound 3 was converted to 2-fluorine derivative 4 in 7steps, which was condensed with N-Boc protected adenine according to thereported protocol of Dey and Gamer, J. Org. Chem., 65:7697 (2000), fromwhich the final nucleoside 15/18 was obtained in three steps. Themonophosphate prodrug 15p/18p was also prepared according to theliterature procedure of McGuigan, et al, J. Med. Chem., 53:4949-4957(2010).

In another synthesis, pursuant to the chemical scheme set forth in thechemical scheme of FIG. 7, compound 15/18 is synthesized from protectedlactum (−) Vince lactum. Each of the steps and reagents used ispresented in the description of FIG. 7, above.

The phosphoamidate prodrug compound 15P/18P was prepared as presented inthe scheme of FIG. 8. In that scheme, the phenylphosphoryldichloride(compound 1P in FIG. 8) is reacted with L-alanine substituted esterhydrochloride in the presence of triethylamine in methylene chloride toproduce the appropriately substituted chlorophenylphorphoryl-L-alaninate(2P or 3P of FIG. 8). Compound 2P or 3P of FIG. 8 is then reacted withcompound 15/18 in N-Methylisoimidazole in solvent (tetrahydrofuran)overnight to produce the prodrug compound 15P/18P or compound 15PU18PI.The experimental procedure for the presentation of the synthesis in FIG.8 is presented in the experimental section. It is noted that thecorresponding ethyl and isobutyl ester analogs of the methyl ester15P/18P and isopropyl ester 15PI/18PI are prepared in the same mannerusing analogous reactants. It is also noted that the phosphorous groupis a chiral center and the presentation in FIG. 8 provides adiastereomeric mixture of 15P/18P and 15PI/18PI. The diastereomericmixture may be separated into purified diastereomers using methodswell-known in the art including selective crystallization (onediastereomer crystallizes out of solution to the exclusion of the otherdiastereomer), chiral column chromatography (HPLC, etc.).

Antiviral Activity against HBV-WT and Mutation Strains

Lamivudine is the first licensed anti-HBV nucleoside which led to thebreakthrough in the field of HBV therapy. The treatment of patients withlamivudine is often associated with significant reduction of serum HBVDNA level and serological conversion and histological improvement incomparison to the placebo groups.^(11,46) However, the rate oflamivudine-resistant mutations is relatively high (70% after 5 yearstreatment), which limits lamivudine's clinical impact.¹¹⁻¹⁴ The primarymutation is rtM204V/I and compensatory mutations are including rtV173L,rtL180M and rtL80I.^(9,10) From a structural perspective, the rtM204V/Iinduced the resistance by means steric hindrance between the side chainof Val/Ile204 and L-sugar ring of lamivudine.^(47,48) Considering thesame L-configuration, telbivudine is inevitably cross-resistant to thelamivudine resistance, such as rtM204I.¹⁵ Another important clinical HBVmutation is rtN236T, which is associated with adefovir therapy at a rateas high as 29% after 5 years treatment.¹⁶⁻¹⁸ Molecule modeling studyindicated that the mutation from Asp to Thr on condon 236 resulted inthe loss of hydrogen bonding between the γ-phosphate ofadefovir-diphosphate and original Asp236, which decreased the bindingaffinity and therefore compromised the antiviral activity of adefoviragainst rtN236T mutant.^(49,50)

In view of the significance of lamivudine- and adefovir-resistantmutations in the clinical application of anti-HBV treatment, thesynthesized nucleoside 15/18 was tested against HBV WT as well aslamivudine- and adefovir-resistant mutants. The screening data aresummarized in Table 1, FIG. 10. Nucleoside 15/10 exhibited a potentantiviral activity against HBV-WT with a 50% effective concentration(EC₅₀) of 1.5 μM and 90% effective concentration (EC₉₀) of 4.5 μM.Interestingly, nucleoside 15/18 is also active againstlamivudine-resistant mutants including rtM204V/I±rtL180M. The foldincrease is around 1.0-1.2, which is comparable to that of adefovir.Furthermore, compound 15/18 did not lose any activity against adefovirmutant (rtN236T) either, with an EC₉₀ value of 4.6 μM.

The structure of 15/18 is analogous to the approved anti-HBV nucleoside,entecavir, except bearing an extra β-fluorine atom on the 2′-position.The conformations of low-energy conformers of two nucleosides are alsosimilar as indicated in our modeling study (vide infra). However, thefluorinated nucleoside 15 is not cross-resistant to all the testedlamivudine-resistant mutants while entecavir lost activity by a fold of8.⁵⁰ Although the detailed mechanism is still unknown, the 2′-fluorinesubstitution may be very important.

The synthesized nucleoside 15/18 was evaluated for its antiviralactivity against wild-type HBV as well as drug resistant mutants invitro, and the results are summarized in Table 1, below. As compound15/18 is a derivative of an adenine analog, the inventors compared theantiviral activity to adefovir instead of entecavir, a guanine analogalthough the carbocyclic moiety is similar to that of entecavir. Fromthe anti-HBV evaluation, the compound 15/18 demonstrated significantanti-HBV activity against wild-type HBV with EC₅₀ value of 1.5 μM. Theantiviral potency was similar to adefovir, while being 7 fold lesspotent than that of lamivudine. The concentration of compound requiredto inhibit 90% (EC₉₀) of HBV DNA in wild-type is 4.5 μM, which is a 1.5fold more potent than that of adefovir (7.1 μM).

Compound 15/18 also showed excellent activity against both lamivudine-and adefovir-associated HBV mutants. It was found that compound 15/18imparts a 4.5-fold enhanced EC₅₀ value (1.7 μM) and a 7.8-fold morefavorable EC₉₀ value (4.6 μM) against adefovir mutant rtN236T. ForrtM204V and rtM204I, compound 18 showed EC₅₀ value of 1.8 and 1.0 μM,respectively. For rtM204V mutant, the potency of adefovir and compound15/18 is similar, but for rtM204I, compound 15/18 was more potent thanthat of adefovir in EC₅₀ as well as EC₉₀ values. For mutant rtL180M, theantiviral activity of compound 15/18 was similar to that of lamivudinein the EC₅₀ value (2.1 vs. 1.5), while it exhibited a 4.3 fold increasedantiviral activity in the EC₉₀ value (5.1 vs. 22.0). Compound 15/18 wasmore potent than that of adefovir against the same mutant in both EC₅₀and EC₉₀ values.

Compound 15/18 was also tested against double mutant rtL180M/rtM204V andit exhibited EC₅₀ value of 2.2 μM, that was equal to that of adefovir,while the EC₉₀ value (5.5 μM) of 15/18 was more effective than that ofadefovir (8.5 μM).

Compound 15/18 was also evaluated against entecavir resistant clone(L180M+S202I+M202V) in which compound 5 demonstrated anti-HBV activity(EC₅₀ 0.67 μM) similar to that of the wild-type virus while in case ofentecavir there is significant decrease its antiviral potency (EC₅₀ 1.2μM) (FIG. 11, Table 2).

Molecular Modeling

It was of interest to know how the compound 15/18 demonstrated thefavorable anti-HBV activity in comparison to that of adefovir.Therefore, molecular modeling studies were conducted to obtain theinsight of the molecular mechanism of compound 15/18 by using theSchrodinger module (1-Second set of references). The homology model ofHBV RT was constructed based on the published X-ray crystal structure ofHIV reverse transcriptase (PDB code: 1RTD), which was previously usedfor molecular mechanism studies of several anti-HBV nucleosides (17). Inthe homology model of HBV polymerase, the relative position of α-, β-and γ-phosphates of compound 15/18 with respect to the catalytic triadwere assumed to occupy the similar position to the dNTP in the crystalstructure of the HIV-1 RT-DNA-dNTP complex. The molecular docking ofcompound 15/18 shows that the triphosphate forms all the network ofhydrogen bonds with the active site residues, S85, A86, A87, R41, K32(FIG. 14 a). The γ-phosphate of 15/18 maintains a critical H-bondingwith the OH of S85 with connection of hydrogen bonds between S85 andN236. Generally, the N236T mutant loses the hydrogen bond to S85, whichresults in destabilization of the S85 to γ-phosphate interaction, thuscauses resistance. However, compound 15/18 (as its triphosphate)maintains a critical H-bonding with S85 (FIG. 14 b) similar to that asobserved in WT (FIG. 14 a).

The carbocyclic ring with an exocyclic alkene of 15/18 occupies thehydrophobic pocket (residues F88, L180 and M204) and makes the favorablevan der Waals interaction with F88 (FIGS. 14 a & 14 b). The 2′-fluorinesubstituent in the carbocyclic ring of 5 appears to promote anadditional binding with R41 as shown in FIGS. 14 a & 14 b, whichcorroborates with the antiviral activity of 15/18 shown in FIG. 10,Table 1. Overall, the modeling studies can qualitatively explain thefavorable anti-HBV activity of the newly discovered compound 15/18 in WT(FIG. 14 a) as well as against adefovir resistant mutant, N236T (FIG. 14b). These modeling studies are informative, and therefore, morequantitative calculation is warranted in the future.

In summary, a novel carbocyclic adenosine derivative 15/18 (FMCA) andits monophosphate prodrug 15P/18P (FMCAP) were synthesized, and theiranti-HBV activity were evaluated. From these studies, both thenucleoside and the prodrug demonstrated significant anti-HBV activityagainst both the wild-type as well as all the major nucleoside-resistantHBV mutants. In view of these promising anti-HBV activities, lowmitochondrial and cellular toxicity as well as the stability againstadenosine deaminase, further biological and biochemical studies of thenucleoside 15/18 and its prodrug 15P/18P are planned to corroborate thein vitro activity in vivo and assess the full potential of these agentsas anti-HBV agents.

The present invention is now described, purely by way of illustration,in the following examples. It will be understood by one of ordinaryskill in the art that these examples are in no way limiting and thatvariations of detail can be made without departing from the spirit andscope of the present invention.

EXAMPLES

Experimental (Chemical Synthesis)

General Methods. Melting points were determined on a Mel-temp IIapparatus and were uncorrected. Nuclear magnetic resonance spectra wererecorded on a Varian Mercury 400 spectrometer at 400 MHz for ¹H NMR and100 MHz for ¹³C NMR or. Varian Inova 500 spectrometer at 500 MHz for ¹HNMR and 125 MHz for ¹³C NMR with tetramethylsilane as the internalstandard. Chemical shifts (□) are reported as s (singlet), d (doublet),t (triplet), q (quartet), m (multiplet), or bs (broad singlet). UVspectra were recorded on a Beckman DU-650 spectrophotometer. Opticalrotations were measured on a Jasco DIP-370 digital polarimeter. Highresolution mass spectra were recorded on a Micromass Autospechigh-resolution mass spectrometer. TLC was performed on Uniplates(silica gel) purchased from Analtech Co. Column chromatography wasperformed using either silica gel-60 (220-440 mesh) for flashchromatography or silica gel G (TLC grade, >440 mesh) for vacuum flashcolumn chromatography. Elemental analyses were performed by AtlanticMicrolab Inc., Norcross, Ga.

(−)-(3aR,4S,6R,6aR)-4-(benzyloxy)-6-(tert-butoxymethyl)-2,2-dimethyl-5-methylenetetrahydro-3aH-cyclopenta[d][1,3]dioxole(4) To a mixture of compound 1 (8.4 g, 34.6 mmol)^(33,34,40) in THFsolution lithium diisopropylamine (2.0 M solution, 19.1 mL, 38.1 mmol)was added slowly at −78° C. After stirring at the same temperature for 3h, Eshenmoser's salt (25.9 g, 138.4 mmol) was added in one portion. Themixture was stirred for additional 3 h at the same temperature andovernight at room temperature. Then iodomethane (108.8 mL, 1.73 mol) wasadded and stirred for 4 h at room temperature before quenching with 10%aqueous NaHCO₃ solution (100 mL). The mixture was stirred for 1 h andextracted with diethyl ether (2×400 mL). The combined ether extractswere washed with 10% aqueous NaHCO₃ followed by brine and dried overanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by vacuum silica gel column chromatography (EtOAc:Hexanes=1:30to 1:10) to give an oil (4.6 g) which was dissolved in MeOH and treatedwith CeCl₃.7H₂O (7.5 g, 19.6 mmol) for 10 min at room temperature. Aftercooling down to −78° C., NaBH₄ (0.75 g, 20.0 mmol) was added slowly. Thereaction was kept at the same temperature for 20 min and quenched withHOAc. Solvent was removed in vacuo and the residue was dissolved inEtOAc and washed with H₂O and brine, dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by vacuumsilica gel column chromatography (EtOAc:Hexanes=1:30 to 1:10) to givewhite solid (4.0 g) which was used directly for next step. White solidcontained from last step (8.0 g, 31.2 mmol) was dissolved in THF andtreated with NaH (60%, 1.62 g, 40.5 mmol) for 15 min at roomtemperature. Benzyl bromide (4.81 mL, 40.5 mmol) and tetrabutylammoniumiodide (TBAI) were added subsequently and the mixture was stirred for3.5 h at 40° C. After quenching with ice/water, the mixture was takeninto Et₂O and washed with H₂O and brine, dried over Na₂SO₄. The solventwas removed under reduced pressure and the residue was purified byvacuum silica gel column chromatography (EtOAc:Hexanes=1:30 to 1:20) togive desired compound 4 (9.7 g, 43% from 1). [α]²⁴ _(D) −121.09° (c0.83, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 7.43-7.26 (m, 5H), 5.28 (d,J=1.0 Hz, 1H), 5.07 (t, J=1.0 Hz, 1H), 4.83 (d, J=12.0 Hz, 1H), 4.68 (d,J=13.0 Hz, 1H), 4.56 (t, J=5.5 Hz, 1H), 4.44 (t, J=1.0 Hz, 1H),4.32-4.30 (m, 1H), 3.42 (dd, J=4.0 and 8.5 Hz, 1H), 3.21 (dd, J=5.0 and8.5 Hz, 1H), 2.59-2.57 (m, 1H), 1.46 (s, 3H), 1.34 (s, 3H), 1.02 (s,9H); ¹³C NMR (125 MHz, CDCl₃) δ 150.6, 138.6, 128.3, 127.8, 127.6,110.8, 108.9, 81.3, 79.7, 78.5, 72.6, 71.8, 64.5, 49.9, 27.3, 26.9,25.3; HR-MS Calcd. for (C₂₁H₃₀O₄+H)⁺ 347.2222, found 347.2225.

(−)-(1S,2S,3S,5R)-3-(benzyloxy)-5-(hydroxymethyl)-4-methylenecyclopentane-1,2-diol(5) Compound 4 (450 mg, 1.3 mmol) was dissolved in MeOH and treated with3 N HCl at refluxed temperature for 3.5 h. After neutralized with solidNaHCO₃, the solvent was removed and the residue was purified by vacuumsilica gel column chromatography (MeOH:CH₂Cl₂=1:30 to 1:10) to givetriol 5 (280 mg, 85%) as a white solid. mp 122-124° C.; [α]²⁴ _(D)−123.05° (c 0.37, MeOH); ¹H NMR (500 MHz, CD₃OD) 57.46-7.30 (m, 5H),5.34 (dd, J=1.0 and 3.0 Hz, 1H), 5.21 (s, 1H), 4.77 (d, J=12.0 Hz, 1H),4.62 (d, J=12.5 Hz, 1H), 4.17-4.14 (m, 2H), 3.95-3.93 (m, 1H), 3.82-3.73(m, 2H), 2.69-2.66 (m, 1H); ¹³C NMR (125 MHz, CD₃OD) δ 148.9, 138.3,128.0, 127.6, 127.3, 109.1, 80.8, 71.7, 71.0, 70.8, 61.8, 49.6; HR-MSCalcd. for (C₁₄H₁₈O₄+H)⁺ 251.1283, found 251.1281.

(−)-(6aR,8S,9R,9aR)-8-(benzyloxy)-2,2,4,4-tetraisopropyl-7-methyleneperhydrocyclopenta[f][1,3,5,2,4]trioxadisilocin-9-ol(6) 1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane (5.5 mL, 16.8 mmol)was added dropwise to a solution of triol 5 (4.0 g, 16.0 mmol) inanhydrous pyridine at −30° C. The reaction mixture was allowed to warmup to room temperature gradually and kept at the same temperature for 2It After removing the pyridine in vacuo, the residue was dissolved inEtOAc and washed with H₂O and brine, dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography on a silica gel (EtOAc:Hexanes=1:30 to 1:5) to yield thealcohol 6 (6.5 g, 82%) as a syrup. [α]²⁴ _(D)-105.94° (c 0.58, CHCl₃);¹H NMR (500 MHz, CDCl₃) δ7.41-7.26 (m, 5H), 5.36 (t, J=2.5 Hz, 1H), 5.11(t, J=2.5 Hz, 1H), 4.77 (d, J=12.0 Hz, 1H), 4.62 (d, J=12.5 Hz, 1H),4.18-4.14 (m, 2H), 4.05 (dd, J=4.5 and 12.0 Hz, 1H), 3.78 (dd, J=8.0 and12.0 Hz, 1H), 2.90-2.88 (m, 1H), 1.08-0.97 (m, 27H); ¹³C NMR (125 MHz,CDCl₃) δ 147.3, 138.1, 128.4, 127.6, 127.5, 111.1, 80.2, 74.2, 71.2,71.1, 64.9, 50.1, 17.6, 17.5, 17.4, 17.3, 17.2, 17.1, 17.0. Anal. Calcd.for C₂₆H₄₄O₅Si₂: C, 63.37; H, 9.00. Found: C, 63.64; H, 9.05.

(−)-(6aR,8S,9R,9aR)-8-(benzyloxy)-2,2,4,4-tetraisopropyl-7-methyleneperhydrocyclopenta[f][1,3,5,2,4]trioxadisilocin-9-ol(7) A solution of compound 6 (2.1 g, 4.3 mmol) and anhydrous pyridine(1.05 mL, 12.6 mmol) in anhydrous CH₂Cl₂ (20 mL) was treated withtrifluoromethanesulfonic anhydride (0.94 mL, 5.6 mmol) at −78° C. Thereaction mixture was allowed to warm up to room temperature graduallyand kept at the same temperature for 20 min. After removing the solventin vacuo, the residue was dissolved in EtOAc and washed with H₂O andbrine, dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was dissolved in anhydrous benzene (40 mL), and 18-crown-6(2.25 g, 8.6 mmol) and cesium acetate (2.47 g, 12.6 mmol) were added.The suspension was heated at 50° C. for 30 min and cooled to roomtemperature. After removing the solvent, the residue was dissolved inthe MeOH and treated with sodium methoxide at room temperature for 3 hand concentrated in vacuo. The residue was purified by columnchromatography on a silica gel (EtOAc:Hexanes=1:10 to 1:3) to give 7(1.7 g, 81% from 6). [α]²⁴ _(D) −76.47° (c 0.82, CHCl₃); ¹H NMR (500MHz, CDCl₃) δ7.41-7.26 (m, 5H), 5.34 (t, J=2.5 Hz, 1H), 5.16 (t, J=2.0Hz, 1H), 4.80 (q, J=12.0 Hz, 2H), 4.12-3.89 (m, 5H), 2.60 (m, 1H),1.09-0.94 (m, 27H); ¹³C NMR (125 MHz, CDCl₃) δ 144.4, 138.6, 128.5,127.7, 127.6, 111.5, 82.4, 82.3, 77.3, 77.0, 76.8, 76.2, 71.8, 62.7,49.4, 17.6, 17.5, 17.4, 17.3, 17.2, 17.1, 17.0, 13.6, 13.4, 12.8, 12.6.HR-MS Calcd. for (C₂₆H₄₄O₅Si₂+H)⁺ 493.2806, found 493.2736.

(−)-(6aR,8S,9R,9aR)-8-(benzyloxy)-9-fluoro-2,2,4,4-tetraisopropyl-7-methylenehexahydrocyclopenta[f][1,3,5,2,4]trioxadisilocine(8) To a solution of alcohol 6 (6.5 g, 13.2 mmol) in anhydrous CH₂Cl₂,(diethylamino)sulfur trifluoride (DAST, 1.84 mL, 13.9 mmol) was addedslowly at room temperature. The reaction mixture was quenched with icedH₂O after 20 min. The organic layer was collected and the aqueous phasewas extracted with dichloromethane. The organic layer was then combined,dried over magnesium sulfate, filtered and concentrated in vacuo. Thecrude residue was used immediately for the next deprotection step. Theanalytic sample of 8 was obtained by the purification using columnchromatography on a silica gel (EtOAc:Hexanes=1:100 to 1:20). [α]²⁴ _(D)−104.08° (c 0.51, CHCl₃); ¹HNMR (500 MHz, CDCl₃) δ7.39-7.26 (m, 5H),5.36 (t, J=2.5 Hz, 1H), 5.20 (dd, J=2.5 and 5.0 Hz, 1H), 4.92 (ddd,J=6.0, 7.5 and 55.0 Hz, 1H), 4.78 (d, J=11.5 Hz, 1H), 4.65 (d, J=11.5Hz, 1H), 4.31-4.26 (m, 1H), 4.23-4.16 (m, 1H), 4.01-3.92 (m, 1H),1.08-0.94 (m, 27H); ¹³C NMR (100 MHz, CDCl₃) □ 142.6 (d, J=9.2 Hz),137.9, 128.4, 127.8, 127.7, 112.7, 103.4 (d, J=189.0 Hz), 80.4 (d,J=21.3 Hz), 73.8 (d, J=19.8 Hz), 71.3, 61.6, 48.8 (d, J=5.3 Hz), 17.5,17.4, 17.1, 17.0, 16.9, 16.8, 13.4, 13.3, 12.7, 12.5. HR-MS Calcd. for(C₂₆H₄₃FO₄Si₂+H)⁺ 495.2762, found 495.2769.

(−)-[(1R,2Ri3R,4R)-2-(benzoyloxy)-4-(benzyloxy)-3-fluoro-5-methylenecyclopentyl]methylbenzoate (9) The crude fluorinated compound 8 (directly from last step)was dissolved in THF and treated with acetic acid (3.2 mL, 53.0 mmol)followed by tetrabutylammonium fluoride (TBAF) (40 mL, 40.0 mmol) atroom temperature for 1 h. After removing the solvent in vacuo, theresidue was dissolved in isopropyl alcohol/chloroform (4:1) co-solventand washed with H₂O. The organic layer was collected, dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography on a silica gel (EtOAc:Hexanes=1:4 to1:1) to give a diol. Dial (1.0 g, 4.0 mmol) was dissolved in anhydrouspyridine and was treated with benzoyl chloride (1.88 mL, 16.0 mmol) atroom temperature. Pyridine was removed in vacuo after 4 h and theresidue was dissolved in EtOAc. The solution was washed with H₂O andbrine, dried over magnesium sulfate, filtered and concentrated under invacuo. The residue was purified by column chromatography on a silica gel(EtOAc:Hexanes=1:20 to 1:3) to give 9 (1.8 g, 61%). [α]²⁴ _(D) −52.71°(c 0.55, CHCl₃); ¹H NMR (500 MHz, CDCl₃) □8.03-7.26 (m, 15H), 5.68-5.61(m, 1H), 5.49 (t, J=2.5 Hz, 1H), 5.34 (dd, J=2.5 and 4.5 Hz, 1H), 5.20(td, J=6.0 and 53.0 Hz, 1H), 4.82 (d, J=11.5 Hz, 1H), 4.73 (d, J=11.5Hz, 1H), 4.62 (dd, J=5.0 and 10.5 Hz, 1H), 4.55-4.50 (m, 2H), 3.24-3.23(m, 1H); ¹³C NMR (125 MHz, CDCl₃) □ 166.3, 165.7, 142.8 (d, J=7.6 Hz),137.5, 133.4, 133.0, 129.8, 129.6, 129.5, 129.3, 128.5, 128.4, 128.3,128.0, 127.9, 114.3, 99.9 (d, J=189.9 Hz), 81.2 (d, J=22.0 Hz), 76.2 (d,J=23.8 Hz), 71.7, 64.9, 45.0 (d, J=4.5 Hz). HR-MS Calcd. for(C₂₈H₂₅FO₅+H)⁺ 461.1764, found 461.1756.

(−)-[(1R,2R,3R,4R)-2-(benzoyloxy)-3-fluoro-4-hydroxy-5-methylenecyclopentyl]methylbenzoate (10) A solution of compound 9 (1.4 g, 3.0 mmol) in anhydrousCH₂Cl₂ was treated with boron trichloride (9.1 mL of 1M solution inCH₂Cl₂, 9.1 mmol) at −78° C. After stirred at the same temperature for30 min, additional portion of boron trichloride (6.1 mL of 1M solutionin CH₂Cl₂, 6.1 mmol) was added. The reaction was quenched with MeOH at−78° C. after another 15 min and concentrated in vacuo. The residue waspurified by column chromatography on a silica gel (EtOAc:Hexanes=1:10 to1:3) to give 10 (1.0 g, 89%) as a syrup. [α]²⁶ _(D)-53.55° (c 0.25,CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ8.03-7.32 (m, 10H), 5.66 (td, J=6.8 and16.4 Hz, 1H), 5.49 (t, J=2.0 Hz, 1H), 5.32 (dd, J=2.0 and 4.4 Hz, 1H),4.96 (td, J=6.8 and 54.4 Hz, 1H), 4.80 (m, 1H), 4.64-4.52 (m, 2H), 3.21(m, 1H), 2.66 (d, J=7.0 Hz, D₂O exchangeable, 1H); ¹³C NMR (125 MHz,CDCl₃) δ 166.3, 165.8, 144.4 (d, J=8.4 Hz), 133.4, 133.1, 129.8, 129.6,129.2, 128.4, 128.3, 113.1, 99.9 (d, J=191.3 Hz), 75.3, 75.2, 75.1,75.0, 65.4, 44.8 (d, J=3.8 Hz). Anal. Calcd. for C₂₁H₁₉FO₅: C, 68.10; H,5.17. Found: C, 67.78; H, 5.27.

(1R,3R,4R,5R)-5-(benzoyloxy)-3-(6-chloro-9H-9-purinyl)-4-fluoro-2-hydroxy-2-(hydroxymethyl)cyclopentyl]methylbenzoate (12) To a solution of compound 10 (1.07 g, 2.89 mmol),triphenylphosphine (TPP, 1.13 g, 4.33 mmol) and 6-chloropurine (0.67 g,4.33 mmol) in anhydrous THF (20 mL) and diisopropyl azodicarboxylate(DIAD, 0.89 mL, 4.33 mmol) was added at 0° C. during 5 min. The reactionwas allowed to warm up to room temperature and kept for 1 h. Thereaction was quenched by adding MeOH (1 mL) and evaporated in vacuo. Theresidue was purified by column chromatography on a silica gel(EtOAc:Hexanes=1:4 to 1:2) to give a coupling nucleoside 11 as a mixturewhich was contaminated with the reduced DIAD species. The crude compound11 (660 mg) was dissolved actone/H₂O (15 mL/2.5 mL) and treated withosmium tetroxide (1.3 mL 5% H₂O solution)/NMO (480 mg) for 24 h. Thereaction mixture was quenched with saturated sodium thiosulfate aqueoussolution. The organic solution was removed in vacuo and the aqueousphase was extracted with isopropyl alcohol/chloroform (4:1) co-solvent.The organic layer was collected and dried over Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo and the residue was purified bycolumn chromatography on a silica gel (MeOH:CH₂Cl₂=1:60 to 1:40) to givecompound 12 as a mixture of diastereomers (640 mg, 41% from 10). Majorisomer: ¹H NMR (500 MHz, CD₃OD) δ 8.80 (d, J=5.0 Hz, 1H), 8.78 (s, 1H),7.95-7.11 (m, 10H), 6.10 (ddd, J=3.0, 12.5 and 17.5 Hz, 1H), 5.80 (dd,J=10.0 and 35.0 Hz, 1H), 5.38 (ddd, J=3.0, 10.5 and 67.5 Hz, 1H), 4.80(m, 2H), 3.73 (d, J=14.5 Hz, 1H), 3.40 (d, J=14.5 Hz, 1H), 3.00 (m, 1H);¹³C NMR (100 MHz, CDCl_(a)) 166.4, 165.6, 153.1, 151.8, 151.7, 149.9,148.2, 148.1, 129.4, 129.1, 128.2, 127.9, 93.1 (d, J=193.1 Hz), 80.8,79.3 (d, J=26.2 Hz), 62.8, 61.9 (d, J=5.0 Hz), 60.2 (d, J=13.4 Hz), 48.6(d, J=5.6 Hz). HR-MS Calcd. for (C₂₆H₂₂ClFN₄O₆+H)⁺ 541.1290, found541.1290.

[(1R,3R,4R,5R)-3-(6-amino-9H-9-purinyl)-5-(benzoyloxy)-4-fluoro-2-hydroxy-2-(hydroxymethyl)cyclopentyl]methylbenzoate (13) Nucleoside 12 (620 mg, 1.15 mmol) in anhydrous DMF wastreated with sodium azide (750 mg, 11.5 mmol) at 70-80° C. for 1.5 h.The volatile was removed in vacuo and the residue was dissolved inisopropyl alcohol/chloroform (4:1) co-solvent and washed with H₂O, driedover Na₂SO₄ and evaporated to dryness. The resulting crude azidecompound was dissolved in EtOH and treated with Pd/C (200 mg) under H₂atmosphere at 40° C. for 3 h. After removing the solid, the filtrate wasevaporated and the residue was purified by column chromatography on asilica gel (MeOH:CH₂Cl₂=1:40 to 1:20) to give desired adenosine analogue13 (370 mg, 62%) as a mixture of diastereomers. Major isomer: UV (MeOH)λ_(max) 259.0 nm; ¹H NMR (500 MHz, CD₃OD) δ 8.43 (d, J=4.0 Hz, 1H), 8.29(s, 1H), 7.99-7.16 (m, 10H), 6.11 (ddd, J=2.5, 9.5 and 14.5 Hz, 1H),5.59 (dd, J=8.0 and 29.0 Hz, 1H), 5.35 (ddd, J=2.5, 8.5 and 43.5 Hz,1H), 4.89 (m, 2H), 3.72 (d, J=11.0 Hz, 1H), 3.50 (d, J=11.0 Hz, 1H),3.00 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ166.4, 165.6, 156.0, 152.4,150.5, 142.8, 142.7, 133.1, 132.7, 129.4, 129.1, 128.2, 127.8, 117.7,93.3 (d, J=193.1 Hz), 80.8, 79.4 (d, J 26.2 Hz), 63.0, 61.9 (d, J=17.6Hz), 60.3, 48.9 (d, J=5.2 Hz). HR-MS Calcd. for (C₂₆H₂₅FN₅O₆+H)⁺5221789, found 5221774.

(+)-[(1R,3R,4R,5R)-3-(6-amino-9H-9-purinyl)-5-(benzoyloxy)-4-fluoro-2-methylenecyclopentyl]methylbenzoate (14) Compound 13 (260 mg, 0.50 mmol) was dissolved in moistacetonitrile (9 μL H₂O was added into 10 mL anhydrous acetonitrile) andcooled to −30° C. Excess 1-bromocarbonyl-methylethylacetate (0.54 mL,3.68 mmol) was added dropwise into the mixture and allowed to warm up tomom temperature. After stirring at room temperature for 1 h, thereaction mixture was again cooled to −30° C. and additional 1bromocarbonyl-methylethylacetate (0.2 mL, 1.47 mmol) was added. Crushedice was added to quenched the reaction and neutralized with saturatedNaHCO₃ (20 mL) solution and extracted with EtOAc (100 mL×2). Thecombined organic layer was washed with brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo and the residue wasdissolved in anhydrous DMF and treated with activated zinc (c.a. 2.0 g)and HOAc (0.2 mL) and stirred at room temperature for 8 h. The volatilewas removed in vacuo and the residue was dissolved in isopropylalcohol/chloroform (4:1) co-solvent and washed with saturated NaHCO₃ (15mL) solution, H₂O and brine. The organic layer was collected and driedover Na₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by column chromatography on a silica gel(EtOAc:Hexanes=2:1 to 4:1) to give exo-cyclic alkene nucleoside 14(165.0 mg, 68%) as a white solid. mp: 195-198° C. (dec.) [□]²⁵ _(D)+77.66° (c 0.27, CHCl₃); UV (MeOH) λ_(max) 231.0, 259.0 nm; ¹H NMR (400MHz, CDCl₃) δ 8.40 (s, 1H), 8.12-8.06 (m, 2H), 7.94 (d, J=3.6 Hz, 1H),7.65-7.44 (m, 3H), 6.0 (dd, J=2.4 and 33.2 Hz, 1H), 5.86 (br, 2H, D₂Oexchangeable), 5.75 (d, (d, J=14.8 Hz, 1H), 5.50 (s, 1H), 5.21 (dd,J=4.0 and 50.8 Hz, 1H), 4.98 (d, J=1.2 Hz, 1H), 4.82-4.64 (m, 1H),4.66-4.6.1 (m, 1H), 3.42 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 166.4,165.0, 155.5, 153.2, 150.5, 144.4, 140.9, 140.8, 133.8, 133.3, 130.0,129.7, 129.6, 128.7, 128.6, 128.5, 118.8, 113.2, 93.6 (d, J=184.4 Hz),75.8 (d, J=29.0 Hz), 64.4 (d, J=3.1 Hz), 58.3 (d, J=17.5 Hz), 46.5.HR-MS Calcd. for (C₂₆H₂₂FN₅O₄+H)⁺ 488.1734, found 488.1731.

(+)-(1R,2R,3R,5R)-3-(6-amino-9H-9-purinyl)-2-fluoro-5-(hydroxymethyl)-4-methylenecyclopentan-1-ol(15) Diisobutylaluminum hydride (DIBAL-H, 1.6 mL, 1.0 M in toluene) wasadded slowly into the solution of compound 14 (160.0 mg, 0.33 mmol) inanhydrous CH₂Cl₂ at −78° C. After 30 min at the same temperature, thereaction was diluted with isopropyl alcohol/chloroform (4:1) co-solvent(30 mL) and saturated potassium sodium tartrate solution (10 mL) wasadded. The mixture was stirred at room temperature for 2 h and theorganic layer was collected. The aqueous layer was extracted withisopropyl alcohol/chloroform (4:1) co-solvent (3×10 mL) and organiclayer were combined, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by columnchromatography on a silica gel (MeOH:CH₂Cl₂=1:20 to1:10) to giveadenosine analogue 15 (70.0 mg, 76%) as a white solid. mp: 215-218° C.(dec.) [α]²⁵ _(D) +151.80° (c 0.23, CHCl₃) UV (H₂O) λ_(max) 259.0 nm (ε13998, pH 2), 260.0 nm (ε 15590, pH 7), 260.0 nm (ε 15579, pH 11); ¹HNMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), 8.06 (d, J=2.4 Hz, 1H), 5.86 (dd,J=2.4 and 25.6 Hz, 1H), 5.42 (t, J=2.4 Hz, 1H), 4.93 (td, J=3.2 and 52.4Hz, 1H), 4.92 (s, 1H, partially buried inside the H₂O peak), 4.40 (td,J=3.2 and 10.8 Hz, 1H), 3.88-3.76 (m, 2H), 2.78 (m, 1H); ¹³C NMR (100MHz, CDCl₃) δ 156.0, 152.5, 149.9, 146.1 (d, J=1.0 Hz), 141.1 (d, J=5.2Hz), 117.9, 111.8, 95.9 (d, J=186.0 Hz), 72.9 (d, J=22.9 Hz), 61.8 (d,J=3.4 Hz), 57.6 (d, J 17.2 Hz), 51.1. Anal. Calcd. for C₁₂H₁₄FN₅O₂: C,51.61; H, 5.05; N, 25.08. Found: C, 51.74; H, 5.09; N, 24.92.

Compound 1.8 (FIG. 5). Compound 18 (identical to compound 15 of scheme2, but synthesized by the alternative route(s) presented in FIG. 5) wassynthesized following one or more of the approaches which are set forthin attached FIG. 5. Selected analytical data for compound 18 wasidentical for that of compound 15, above.

Experimental Protocol for Compounds 15P/18P and 15PI/18PI

N-Methylimidazole (NMI, 5.0 mmol) was added to a stirring suspension ofFMCA (1 mmol) in dry THF under argon atmosphere at −78° C. Theappropriate substituted chlorophenylphosphoryl-L-alaninate (2P or 3P,3.0 mmol) dissolve in THF was added dropwise, slowly heated up to roomtemperature and continue stirred over night at it Volatiles wasevaporated, and the residue was dissolved in dichloromethane (DCM) andwashed with 0.5 M HCL. The organic layer dried over Na₂SO₄ iltered,reduced to dryness, and purified by flash chromatography to give theprodrug of FMCA (15/18 & 15P/18P).

Analytical data of compound 15P/18P ¹H NMR (500 Mz, CD₃OD) d 8.35 (s,1H), 7.86 (d, J==3.0 Hz, 1H), 7.34-7.15 (m, 5H), 5.95 (m, 3H), 5.26 d,J=8.0 Hz, 1H), 5.01-4.90 (m, 1H), 4.83 (s, 1H), 4.50-4.41 (m, 2H),4.25-4.04 (m, 3H), 3.71 (s, 3H), 3.07 (s, 1H), 1.40 (d, J 6.5 Hz, 3H);¹⁹F NMR (500 MHz, CDCl₃) δ −192.86 (m, 1F); ¹³C NMR (125 MHz, CD₃OD)d171, 159.0, 156.5, 152.5, 150.4, 142.9, 130.1, 121.2, 120.3, 106.7,102.4, 72.2, 71.1, 62.3, 51.9, 46.3, 43.9, 19.1; ³¹P NMR (CDCl₃, 202MHz): δ 2.67, 2.99. Anal. Calcd. For C₂₂H₂₆FN₆O₆P.0.5H₂O: C, 49.91; H,5.14; N, 15.87. Found C, 49.84; H, 5.06; N, 15.22.

Analytical Data of compound 15PI/18PI ¹H NMR (500 Mz, CD₃OD) d 8.36 (s,1H), 7.84 (d, J=30.0 Hz, 1H), 7.34-7.07 (m, 5H), 5.94 (d, J=23 Hz, 1H),5.76 (bs, 2H NH₂), 5.30 (m, 1H), 5.04-4.86 (m, 3H), 4.50-4.44 (m, 2H),4.21 (m, 1H), 4.11-3.80 (m, 3H), 3.09 (s, 1H), 1.40 (d, J=14.5 Hz, 3H),1.28 (d, J=14.0 Hz, 6H); ¹⁹F NMR (500 MHz, CDCl₃) δ −192.96 (m, 1F); ³¹HNMR (CDCl₃, 202 MHz): δ 2.84, 2.32.

Antiviral Assay

Drug susceptibility assays were performed as previously described.Cytotoxicity assays in PBM, CEM and Vero cells were conducted aspreviously described. Two compounds were used for, testing, the first,an adenine nucleoside analog which contained hydroxyl groups at R¹ andR^(1a) on the sugar portion of the molecule (compound 15/18) and thesecond, a prodrug nucleoside compound 15P/18P which is based uponcompound 15/18 which contained a phosphoamidate group on R¹ (R^(1a) wasH) containing a phenyl group as R⁶ and B′ was an amino acid groupderived from alanine, where R⁸ was methyl and R″ was a methyl group,forming a methyl ester. These compounds were tested in a standard HBVassay in the laboratory of Dr. Brent Korba. The following results wereobtained. Note that the compounds according to the present inventiontested were more than 1000 fold more potent than was 3TC in this assay.The prodrug compound (second compound tested where R¹ was aphosphoamidate group R⁶=phenyl and B′ was derived from alanine andcontained a methyl ester (R⁸ is methyl and R″ is methyl) was more than10 times more active than the compound where both R¹ and R^(1a) are H.

HBV Assay Results

Test Control: 3TC (μM) Number CC50 EC50 EC90 Sl EC50 1 >300 0.548 6 >502421 2 >300 0.062 0.462 >649 2421

As previously described, Compound 15/18 was also tested againstwild-type and drug resistant forms of HBV. The testing is describedabove and the results are presented in Table 1, which is set forth inattached FIG. 10 hereof.

A mono-phosphate prodrug can be useful not only to bypass the ratelimiting initial phosphorylation step by the nucleoside kinase, therebyto increase the antiviral potency, but also it may potentially targetthe liver. Therefore, a phosphoramidite, compound 15P/18P was alsosynthesized. In separate antiviral evaluation experiments, it wasobserved that the anti HBV potency of 15P/18P in vitro was enhanced 7-and 13-fold in the EC₅₀ and EC₉₀ value, respectively, against WT HBV incomparison to the parent compound 15/18 without significant increase ofcellular toxicity (Table 2, FIG. 11). The mono-phosphate prodrug 15P/18P(IC₅₀=0.05 μM) was also evaluated against HBV genotype C entecavirresistant clone (L180M+M204V+S202G) in Huh7 cells (16) as shown in FIG.11, Table 2, and interestingly the compounds 15/18 and 15P/18P stillmaintain the antiviral potency against the entecavir mutant. FIG. 12shows the anti-HBV activity of Prodrug 15P/18P against HBV genotype Centecavir resistant clone (L180M+S202G+M204V) in Huh7 cells.

Mitochondrial Study

Mitochondrial toxicity studies in HepG2 cells by measuring the lacticdehydrogenase release (13) suggest that FMCA 15/18 did not exhibit anysignificant toxicity up to 100 μM as in lamivudine (3TC), whileazidothymidine (AZT) shows significant toxicity (FIG. 13). In addition,deamination studies with adenosine deaminase from calf thymus indicatedthat compound 15/18 was completely stable (20).

Molecular Modeling Study

Conformational search: The initial conformations of compound 15/18 andentecavir analog 16 were constructed by builder module in MACROMODEL®,version 8.5 (Schrodinger, Inc.) The Monte Carlo conformational searchwas performed in 5,000-step, in the presence of GB/SA water model usingMMFFs force field in MACROMODEL®. Pseudorotation analysis: The onlinepesudorotation analysis tool PROSIT (http://cactus.nci.nih.gov/prosit/)was used to calculated all the pseudorotation parameters.⁵¹

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The invention claimed is:
 1. A nucleoside compound according to thestructure:

Where B is

Wherein R is H, F, Cl, Br, I, C₁-C₄ alkyl (preferably CH₃), —C≡N,—C≡C—R_(a),

X is H, C₁-C₄ alkyl (preferably, CH₃), F, Cl, Br or I; R_(a) is H or a—C₁-C₄ alkyl group; R¹ and R^(1a) are each independently, H, an acylgroup, a C₁-C₂₀ alkyl or ether group, an amino acid residue (D or L), aphosphate, diphosphate, triphosphate, phosphodiester or phosphoramidategroup or together R¹ and R^(1a) form a carbodiester or phosphodiestergroup with the oxygen atoms to which they are bonded; R² is H, an acylgroup, a C₁-C₂₀ alkyl or ether group or an amino acid residue (D or L);Or a pharmaceutically acceptable salt, or enantiomer thereof.
 2. Thecompound according to claim 1, wherein R^(1a) is H.
 3. The compoundaccording to claim 1 wherein R¹ and R² are each independently H or aC₂-C₂₀ acyl group.
 4. The compound according claim 1 wherein R¹, R^(1a)and R² are each H.
 5. The compound according to claim 1 wherein B is


6. The compound according to claim 1 which is represented by thechemical structure:


7. The compound according to claim 6 wherein B is


8. The compound according to claim 6 wherein R¹, R^(1a) and R² are eachindependently H or a C₂-C₂₀ acyl group.
 9. The compound according toclaim 1 wherein R is H or F.
 10. The compound according to claim 1wherein R^(1a) is H and R¹ and R² are each independently H or a C₂-C₂₀acyl group.
 11. The compound according to claim 1 wherein R¹ is an acylgroup, a phosphate, phosphodiester or phosphoramidate group.
 12. Thecompound according to claim 1 wherein R¹ together with the nucleoside towhich it is attached forms a group according to the structure:

where each R⁵ and R⁶ is independently selected from H, a C₁ to C₂₀linear, branched or cyclic alkyl group, alkoxyalkyl, aryloxyalkyl, aryl,alkoxy or alkoxycarbonyloxy group, each of which groups may beoptionally substituted, with the proviso that at least one R⁵ group isother than H, or the two R⁵ groups together form a five- or six-memberedheterocyclic group; B′ is a group according to the structure

Where i is 0, 1, 2 or 3; R⁷ is a C₁ to C₂₀ linear, branched or cyclicalkyl, acyl, alkoxyalkyl, aryloxyalkyl or aryl group, each of whichgroups may be optionally substituted; R⁸ is a sidechain of an aminoacid; and Each R″ is independently a C₁ to C₂₀ linear, branched orcyclic alkyl or, a phenyl or heteroaryl group, each of which groups maybe optionally substituted.
 13. The compound according claim 1 wherein R¹and R^(1a) together with the nucleoside to which those groups areattached form a group according to the structure:

where R⁶ is selected from H, a C₁ to C₂₀ linear, branched or cyclicalkyl group, alkoxyalkyl, aryloxyalkyl, aryl and alkoxy.
 14. Thecompound according to claim 1 wherein R¹, together with the nucleosideto which it, is attached is a group according to the structure:

Where R⁶ is a C₁-C₂₀ alkyl or an optionally substituted phenyl group; B′is a group according to the structure

Where R^(B) is a C₁-C₃ linear or branch-chained alkyl group; and R″ is aC₁-C₂₀ linear, cyclic or branch-chained alkyl group or an optionallysubstituted phenyl group.
 15. The compound according claim 14 wherein Bis

R² and R^(1a) are each independently H or a C₂-C₂₀ acyl group; R¹,together with the nucleoside to which it is attached is a groupaccording to the structure:

Where R₆ is an optionally substituted phenyl group; and B′ is a groupaccording to the structure

Where R⁸ is methyl; and R″ is a C₁-C₄ linear or branch-chained alkylgroup.
 16. A compound according to claim 7 wherein R² and R^(1a) areeach independently H or a C₂-C₂₀ acyl group; and R¹ is a

group; Where R_(p1) is an optionally substituted C₁-C₂₀ alkyl group; andR^(P) is H, nitro, cyano, methoxy, or a C₁-C₃ alkyl group optionallysubstituted with from 1-3 halogen substituents.
 17. The compoundaccording to claim 16 wherein R′ is

Where R^(P) is H or C₁-C₃ alkyl group and R_(p1) is methyl, ethyl,isopropyl or isobutyl.
 18. The compound according to claim 17 whereinR^(p) is H and R_(p1) is methyl or isopropyl.
 19. The compound accordingto claim 16 wherein R¹ is a

group, Where R^(P) is H or C₁-C₃ alkyl group.
 20. The compound accordingto claim 17 wherein R^(p) is H.
 21. The compound according to claim 16wherein R_(p1) is a C₁-C₄ alkyl group.
 22. The compound

or a pharmaceutically acceptable salt or enantiomer thereof.
 23. Apharmaceutical composition comprising an effective amount of a compoundaccording to claim 1, optionally in combination with a pharmaceuticallyacceptable carrier, additive or excipient.
 24. The pharmaceuticalcomposition according to claim 23 comprising an effective amount of anadditional antiviral agent.
 25. The composition according to claim 24wherein said additional antiviral agent is acyclovir, famciclovir,ganciclovir, valaciclovir, vidaribine, ribavirin, zoster-immune globulin(ZIG), lamivudine, adefovir dipivoxil, entecavir, telbivudine,clevudine, tenofovir or a mixture thereof.
 26. The composition accordingto claim 24 wherein said additional antiviral agent is selected from thegroup consisting of Hepsera (adefovir dipivoxil), lamivudine, entecavir,telbivudine, tenofovir, erntricitabine, clevudine, valtoricitabine,amdoxovir, pradefovir, racivir, nitazoxanide, Bay 41-4109, EHT899,zadaxin (thymosin alpha-1), NM 283, VX-950 (telaprevir), SCH 50304,TMC435, VX-500, SCH503034, ITMN-191 (R7227), R7128, MK-7009, MK-0608,A-837093, GS 9191, PSI-7851, and mixtures thereof.
 27. The compositionaccording to claim 24 wherein said additional antiviral agent isselected from the group consisting of Hepsera (adefovir dipivoxil),lamivudine, entecavir, telbivudine, tenofovir, erntricitabine,clevudine; valtoricitabine, amdoxovir, pradefovir, racivir,nitazoxanide, Bay 41-4109, EHT899, zadaxin (thymosin alpha-1) andmixtures thereof.
 28. The composition according to claim 24 wherein saidadditional antiviral agent is selected from the group consisting of NM283, VX-950 (telaprevir), SCH 50304, TMC435, VX-500, SCH503034, ITMN-191(R7227), R7128, MK-7009, MK-0608, A-837093, GS 9190, PSI-7851, andmixtures thereof.
 29. A composition according to claim 23 further incombination with at least one anticancer, agent.
 30. The compositionaccording to claim 29 wherein said anticancer agent is selected from thegroup consisting of oxaliplatin, 5-fluorouracil, gemcitabine or mixturesthereof.
 31. The composition according to claim 29 wherein saidanticancer agent is an antimetabolite, an inhibitor of topoisomerase Ior II, alkylating agents or a microtubule inhibitor.
 32. The compositionaccording to claim 29 wherein said anticancer agent is selected from thegroup consisting of Aldesleukin; Alemtuzumab; alitretinoin; allopurinol;altretamine; amifostine; anastrozole; arsenic trioxide; Asparaginase;BCG Live; bexarotene capsules; bexarotene gel; bleomycin; busulfanintravenous; busulfan oral; calusterone; capecitabine; carboplatin;carmustine; carmustine with Polifeprosan 20 Implant; celecoxib;chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine;cytarabine liposomal; dacarbazine; dactinomycin; actinomycin D;Darbepoetin alfa; daunorubicin liposomal; daunorubicin, daunomycin;Denileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicinliposomal; Dromostanolone propionate; Elliott's B Solution; epirubicin;Epoetin alfa estramustine; etoposide phosphate; etoposide (VP-16);exemestane; Filgrastim; floxuridine (intraarterial); fludarabine;fluorouracil (5-FU); fulvestrant; gemeitabine, gemtuzumab, ozogamicin;gleevac, goserelin acetate; hydroxyurea; Ibritumomab Tiuxetan;idarubicin; ifosfamide; imatinib mesylate; Interferon alfa-2a;Interferon alfa-2b; irinotecan; letrozole; leucovorin; levamisole;lomustine (CCNU); meclorethamine (nitrogen mustard); megestrol acetate;melphalan (L-PAM); mercaptopurine (6-MP); mesna; metbotrexate;methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolonephenpropionate; Nofetumomab; LOddC; Oprelvekin; oxaliplatin; paclitaxel;pamidronate; pegademase; Pegaspargase; Pegfilgrastim; pentostatin;pipobroman; plicamycin; mithramycin; porfimer sodium; procarbazine;quinacrine; Rasburicase; Rituximab; Sargramostim; streptozocin;talbuvidine (LDT); talc; tamoxifen; temozolomide; teniposide (VM-26);testolactone; thioguanine (6-TG); thiotepa; topotecan; toremifene;Tositumomab; Trastuzumab; tretinoin (ATRA); Uracil Mustard; valrubicin;valtorcitabine (monoval LDC); vinblastine; vinorelbine; zoledronate; andmixtures thereof.
 33. A kit comprising a composition according to claim23 and instructions to administer said composition to a patient in need.34. A method of treating a viral infection caused by a viral agentselected from the group consisting of Hepatitis B virus (HBV), HepatitisC virus (HCV), Herpes Simplex 1 (HSV-1), Herpes Simplex 2 (HSV-2),cytomegalovirus (CMV), Varicella Zoster virus (VZV) and Epstein Barrvirus (EBV) in a patient in need of therapy comprising administering tosaid patient an effective amount of a compound according to claim
 1. 35.The method according to claim 34 wherein said viral infection is causedby HBV or HCV.
 36. The method according to claim 34 wherein the viralinfection is caused by HBV.
 37. The method according to claim 34 whereinsaid HBV is a drug resistant strain of HBV.
 38. The method according toclaim 35 wherein said HBV strain is resistant to at least one oflamivudine, entecavir and adefovir.
 39. The method according to claim 38wherein said HBV strain is resistant to lamivudine and entecavir. 40.The method according to claim 38 wherein said HBV strain is resistant tolamivudine and adefovir.
 41. The method according to claim 38 whereinsaid HBV strain is resistant to entecavir and adefovir.
 42. The methodaccording to claim 38 wherein said HBV strain is resistant tolamivudine, entecavir and adefovir.
 43. The method according to claim 37wherein said drug resistant strain of HBV is a multiple drug resistantstrain of HBV.
 44. The method according to claim 37 wherein said HBVstrain is rtM204V, rtM204I, rtL180M, rtLM/rtMV, rtN236T orL180M+M204V+S202G.
 45. The method according to claim 44 wherein said HBVstrain is L180M+M204V+S202G.
 46. The method according to claim 34wherein said viral infection is caused by HCV.
 47. A method of treatinga viral infection caused by Hepatitis B virus (HBV) in a patient in needof therapy comprising administering to said patient an effective amountof a composition according to claim
 23. 48. The method according toclaim 47 wherein said HBV is a drug resistant strain of HBV.
 49. Themethod according to claim 47 wherein said HBV is a multiple drugresistant strain of HBV.
 50. The method according to claim 48 whereinsaid drug resistant strain of HBV is rtM204V, rtM204I, rtL180M,rtLM/rtMV, rtN236T or L180M+M204V+S202G.
 51. The method according toclaim 48 wherein said HBV is resistant to at least one of lamivudine,entecavir and adefovir.
 52. The method according to claim 51 whereinsaid HBV is resistant to lamivudine and entecavir.
 53. The methodaccording to claim 51 wherein said HBV is resistant to lamivudine,entecavir and adefovir.
 54. A method of treating a viral infectioncaused by Hepatitis C virus (HCV) in a patient in need of therapycomprising administering to said patient an effective amount of acomposition according to claim
 23. 55. A method of reducing thelikelihood of a viral infection caused by Hepatitis C virus (HCV) in apatient in need of therapy comprising administering to said patient aneffective amount of a composition according to claim
 23. 56. A method oftreating liver fibrosis, cirrhosis or cancer secondary to a HBVinfection in a patient in need thereof comprising administering to saidpatient an effective amount of a composition according to claim
 23. 57.The method according to claim 56 wherein said HBV is a drug resistantstrain of HBV.
 58. The method according to claim 57 wherein said HBVstrain is resistant to one or more of lamivudine, entecavir andadefovir.
 59. The method according to claim 58 wherein said drugresistant strain, of HBV is rtM204V, rtM204I, rtL180M, rtLM/rtMV,rtN236T or L180M+M204V+S202G.
 60. The method according to claim 58wherein said drug resistant strain of HBV is L180M+M204V+S202G.
 61. Themethod according to claim 57 wherein cancer occurs secondary to said HBVor HCV infection and said compound is coadministered with an anticanceragent.
 62. The method according to claim 61 wherein said cancer ishepatocellular cancer.
 63. The method according to claim 62 wherein saidanticancer agent is selected from the group consisting of5-fluororuracil, gemcitabine and oxaliplatin.
 64. A method of reducingthe likelihood that an HBV or HCV infection in a patient willdeteriorate to liver fibrosis, cirrhosis or liver cancer secondary tosaid infection in a patient comprising administering to said patient aneffective amount of a composition according to claim 23 to said patient.65. The method according to claim 64 wherein said composition iscoadministered with at least one anticancer agent.
 66. The methodaccording to claim 65 wherein said HBV is a drug resistant strain ofHBV.
 67. The method according to claim 56 wherein said HBV strain isresistant to at least one or more of lamivudine, entacavir and adefovir.68. The method according to claim 67 wherein said drug resistant strainof HBV is rtM204V, rtM204I, rtL180M, rtLM/rtMV, rtN236T orL180M+M204V+S202G.
 69. The method according to claim 67 wherein saiddrug resistant strain of HBV is L180M+M204V+S202G.
 70. The methodaccording to claim 34 wherein said patient is a human.
 71. Apharmaceutical composition comprising an effective amount of a compoundaccording to claim 22, optionally in combination with a pharmaceuticallyacceptable carrier, additive or excipient.
 72. The pharmaceuticalcomposition according to claim 71 wherein said compound is

or a pharmaceutically acceptable salt thereof.
 73. The pharmaceuticalcomposition according to claim 71 wherein said compound is

or a pharmaceutically acceptable salt thereof.
 74. The compositionaccording to claim 71 comprising an effective amount of an additionalantiviral agent.
 75. The composition according to claim 74 wherein saidadditional antiviral agent is acyclovir, famciclovir, ganciclovir,valaciclovir, vidaribine, ribavirin, zoster-immune globulin (ZIG),lamivudine, adefovir dipivoxil, entecavir, telbivudine, clevudine,tenofovir or a mixture thereof.
 76. The composition according to claim74 wherein said additional antiviral agent is selected from the groupconsisting of Hepsera (adefovir dipivoxil), lamivudine, entecavir,telbivudine, tenofovir, emtricitabine, clevudine, valtoricitabine,amdoxovir, pradefovir, racivir, nitazoxanide, Bay 41-4109, EHT899,zadaxin (thymosin alpha-1), NM 283, VX-950 (telaprevir), SCH 50304,TMC435, VX-500, SCH503034, ITMN-191 (R7227), R7128, MK-7009, MK-0608,A-837093, GS 9190, PSI-7851, and mixtures thereof.
 77. The compositionaccording to claim 74 wherein said additional antiviral agent isselected from the group consisting of Hepsera (adefovir dipivoxil),lamivudine, entecavir, telbivudine, tenofovir, emtricitabine, clevudine,valtoricitabine, amdoxovir, pradefovir, racivir, nitazoxanide, Bay41-4109, EHT899, zadaxin (thymosin alpha-1) and mixtures thereof.
 78. Amethod of treating a viral infection caused by Hepatitis B virus (HBV)in a patient in need of therapy comprising administering to said patientan effective amount f a composition according to claim
 71. 79. Themethod according to claim 78 wherein said HBV is a drug resistant strainof HBV.
 80. The method according to claim 78 wherein said HBV is amultiple drug resistant strain of HBV.
 81. The method according to claim79 wherein said drug resistant strain of HBV is rtM204V, rtM204I,rtL180M, rtLM/rtMV, rtN236T or L180M+M204V+S202G.
 82. The methodaccording to claim 79 wherein said drug resistant HBV is resistant to atleast one of lamivudine, entecavir and adefovir.
 83. The methodaccording to claim 79 wherein said drug resistant HBV is resistant tolamivudine and entecavir.
 84. The method according to claim 79 whereinsaid drug resistant HBV is resistant to lamivudine, entecavir andadefovir.